[Frontiers in Bioscience S1, 275-295, June 1, 2009]]
Neurochemical and behavioral responses to inflammatory immune stressors
Julie Gibb, Marie-Claude Audet, Shawn Hayley, Hymie Anisman
Institute of Neurosciences, Carleton University, Ottawa, Ontario
TABLE OF CONTENTS
1. ABSTRACT
Activation of the inflammatory immune system has been associated with the development of psychological disorders such as major depressive disorder (MDD). In this regard, the release of pro-inflammatory cytokines (signaling molecules of the immune system) provokes a constellation of neurochemical and behavioral alterations, reminiscent of the effects of traditional stressors, which if sustained could influence psychological functioning. In animal models, exogenously administered cytokines, as well as bacterial endotoxins and viral analogues, induce a variety of behavioral disturbances collectively known as sickness behavior. Although it is difficult to differentiate the general malaise of sickness engendered by cytokines from the depressogenic effects, clinical studies have revealed increased levels of circulating cytokines and acute phase proteins in patients diagnosed with MDD. Furthermore, the incidence of MDD is increased in patients suffering from chronic inflammatory conditions, and immunotherapy used to treat chronic illnesses such as Hepatitis C was related to high levels of depression that could be attenuated by antidepressant treatment. Together, these findings indicate that activation of the inflammatory immune system may favor the evolution of psychological disturbances.
2. INTRODUCTION
Stressful experiences may favor the development of anxiety and of major depressive disorder (MDD). It is thought that these pathological outcomes stem, at least in part, from several neurochemical changes, including alterations of monoamine and corticotrophin-releasing hormone (CRH) functioning, as well as disturbances of growth factors such as brain-derived neurotrophic factor (BDNF) (1, 2). Of course, the impact of stressors varies appreciably among both humans and rodents, and several organismic (age, gender, genetic) and experiential factors are responsible for the diverse effects observed (e.g., 3).
It has been argued that activation of the inflammatory immune system engenders stress-like effects and may thus contribute to MDD, and that cytokines (signaling molecules between immune cells) may be essential in mediating this relationship (1, 4-6). Support for this perspective has come from several lines of inquiry, including (a) animal studies indicating that cytokine manipulations may engender behaviors and brain neurochemical alterations that are consistent with those thought to be associated with MDD (7), (b) studies, in humans, showing that MDD is accompanied by elevated levels of several circulating cytokines, acute phase proteins, and inflammatory factors (5), (c) occurrence of depressive symptoms was increased among patients with chronic inflammatory and autoimmune pathologies (8), (d) cytokine immunotherapy (using mainly interferon-alpha; IFN-a) in the treatment of hepatitis C and some forms of cancer may promote depressive illness in a large portion of patients, and that these effects can be attenuated by antidepressant medication (6, 9), and (e) the effects of IFN-a were particularly notable among patients with a history of depression, those who have the lowest tryptophan levels and individuals that exhibit the greatest cytokine variations (9).
The neurochemical changes exerted by pro-inflammatory cytokines are in many ways reminiscent of those associated with stressors, and it has been suggested that activation of the inflammatory immune system might be interpreted by the brain as a stressor (1). Of course, the consequences of psychological and physical stressors are not identical to those associated with systemic immune insults. In fact, even though cytokines, such as interleukin-1beta (IL-1b) and tumor necrosis factor-alpha (TNF-a) and traditional stressors have common effects (e.g., hypothalamic-pituitary-adrenal (HPA) activation), they may do so through different neural circuits (10). Furthermore, the cognitive changes associated with conventional stressors (e.g., shame, loss) would not occur with systemic stressors, such as cytokine activation. Yet, it is possible that the impact of systemic stressors may vary as a function of the background conditions upon which they are imposed. By example, the effects of IFN-a immunotherapy among individuals with severe diseases (e.g., cancer, hepatitis C) might not be the same as they are among individuals not experiencing major life disruption. Likewise, as already alluded to, IFN-a immunotherapy may have more profound effects among individuals disposed toward depression, or at least those with a negative cognitive perspective.
The processes by which cytokines promote depressive symptoms remain to be identified. Nevertheless, it has provisionally been suggested that the depressogenic effects of cytokines may stem from the effects of pro-inflammatory cytokines on central neurotransmitter and growth factors that may be related to depression (e.g., CRH, 5-HT and BDNF), as well as on enzymatic pathways involved in the production of oxidative species and other neurodegenerative factors (1, 7). The current review is meant to provide a broad perspective pertaining to the depressogenic effects associated with cytokine activation. However, as studies in humans do not permit analyses of cytokine effects on brain neurochemical processes, and studies in animals do not readily allow for the differentiation between sickness versus depressive affect elicited by immune activation, the present review borrows from both lines of research to derive a picture concerning the impact of immune activation on depressive-like illness. In this regard, we attempt to identify whether specific patterns of inflammatory immune activation are related to distinct components of the depressive profile.
3. CYTOKINE INFLUENCES ON THE CENTRAL NERVOUS SYSTEM
3.1. Cytokines within the brain
Circulating cytokines are ordinarily maintained at low levels, and they usually act in an autocrine (local cellular actions, operating in a feedback capacity) or paracrine (acting upon cells in proximity of where they are produced) manner at lymphoid organs, such as the spleen, lymph nodes or liver (11). Although cytokine spillover into circulation is typically diluted rapidly, in response to strong immunological challenge, circulating levels of pro-inflammatory cytokines are markedly increased (12). The increased cytokine activity may provoke release of acute phase proteins and elevated utilization of steroidal hormones (9).
As cytokines are large molecules, their access to the brain is relatively limited, but they may enter the brain at sites where the blood-brain barrier (BBB) is less efficient, such as at circumventricular organs (median eminence, subfornical organ, area postrema, organum vasculosum). It has also been reported that saturable transport mechanisms are present that serve to move cytokines (IL-1b and TNF-a) into the brain (13, 14). Significantly, immunologic challenges, cytokines, and stressors may compromise the integrity of the BBB, and might thus increase passage of cytokines into the brain (15, 16).
Having gained access to the brain, cytokines may stimulate receptors on cells lining the BBB, around the meninges as well as vascular areas of the brain (17). Ultimately, cytokines may reach hypothalamic, amygdaloid and brain stem nuclei where they interact with appropriate receptors that are present (18, 19). In addition, cytokines stimulate secondary mediators, such as prostaglandins, that may promote the central neurochemical effects of cytokines.
The actions of cytokines in the brain are not restricted to those that come from circulation, but may also reflect actions of cytokines endogenously synthesized in brain microglia and possibly in neurons as well. In this regard, both pro- and anti-inflammatory cytokine levels are elevated following traumatic insults (20-22), endotoxin and cytokine treatments (23-25), stroke and neurotoxins (21, 22, 26) and by neurogenic and psychogenic stressors (22, 27-29). These endogenous cytokines, like those derived from peripheral sources, could potentially act upon neurotransmission, and might thus affect behavioral outputs.
3.2. Neurochemical effects of cytokines
When administered systemically, bacterial endotoxins, as well as recombinant cytokines, markedly influence various hormonal and neurotransmitter processes, including those that are activated by psychological and physical stressors (1). Of the varied consequences of cytokine treatments, the best studied have been concerned with the marked activation of the HPA axis that culminates in the rise of circulating glucocorticoids. Like traditional stressors, pro-inflammatory cytokines, including IL-1b and TNF-a, increase the CRH mRNA expression at the paraventricular nucleus of the hypothalamus (PVN), and also increase the expression of CRH at the central amygdala (7). Although IL-1b, TNF-a, and IL-6 all promote these neuroendocrine alterations, IL-1b is the most potent in this respect, and it generally appeared that IL-6 was least potent (30).
Like stressors, cytokines markedly influence central neurotransmitter activity. Specifically, IL-1b increased the utilization of serotonin (5-HT) and norepinephrine (NE) within several stressor-sensitive brain regions, including the PVN, medial prefrontal cortex (mPFC), and central amygdala (31-34). Such effects have been detected in analyses of postmortem tissues, and cytokine-induced release of these neurotransmitters was also shown in vivo within both the hypothalamus and hippocampus (35-39).
Analyses of the neurochemical effects of cytokines have largely focused on that of IL-1b and to a lesser extent on IL-6 and TNF-a. In light of the clinical applications of IFN-a there has been research, albeit relatively limited, assessing the biological and behavioral effects of this cytokine (40). It has been shown that IFN-a dose-dependently increased plasma corticosterone levels, although these effects were far less pronounced than those elicited by IL-1b (41). In rodents, the effects of IFN-a declined with repeated administration (42), and in humans the increased circulating IFN-a associated with acute administration (43, 44) was not apparent with repeated treatment (45).
Like other cytokines, administration of IFN-a increased hypothalamic and hippocampal NE utilization as well as that of the amino acid transmitters, gamma-aminobutyric acid (GABA) and glutamate (42, 46). This cytokine also reduced dopamine (DA) concentrations within the amygdala (47), although it is uncertain whether this stemmed from excessive utilization or reduced synthesis. In vitro studies have also revealed that IFN-a stimulated CRH release from amygdala and hypothalamic neurons (48).
Inasmuch as systemic IFN-a administration provoked central neurochemical changes, it should not be surprising to find that when IFN-a was administered directly into the brain, changes of hypothalamic neuronal firing were apparent (49). This treatment also increased hippocampal DA activity (50, 51), increased mRNA expression of the 5-HT transporter (5-HTT) (51), but reduced 5-HT concentrations in the PFC (50). Interestingly, IFN-a administration also engendered 5-HT2C receptor mRNA editing (52), paralleling reports that such an effect was associated with anxiety and depressive symptoms in animal models (53), and reports that altered 5-HT2C editing was associated with depression/suicide (54, 55).
As previously described (1), there are several routes by which pro-inflammatory cytokines might affect 5-HT functioning, and hence depression. Specifically, the 5-HT changes may be secondary to CRH variations elicited by cytokines (7), or may be secondary to changes of growth factors (e.g., BDNF) that have been implicated in MDD (1). As well, cytokines, such as IFN-a may stimulate indoleamine-2,3-dioxygenase (IDO) and GTP-cyclohydrolase activity, which provoke degradation of the 5-HT precursor, tryptophan (56), hence reducing 5-HT functioning (57). In this regard, IFN-a also promotes metabolism of tryptophan into kynurenine and then into the oxidative metabolites, 3-hydroxy-kynurenine and quinolinic acid (which themselves are increased in depression), which may provoke neurotoxicity (58, 59). The generation of free radicals provoked by these kynurenine metabolites may also be related to neurodegenerative diseases, including Alzheimer's and Parkinson's, and might account for the comorbidity of these illnesses with MDD.
In closing this section it ought to be emphasized that activation of the inflammatory immune system, whether in response to pathogens or in the treatment of pathology, typically occurs on a chronic or subchronic basis. Yet, the vast majority of studies assessing the impact of cytokines have focused on the acute effects of these treatments (possibly owing to the prohibitive cost of recombinant cytokines). Unfortunately, the few studies that have addressed this have not yielded unequivocally consistent results. For instance, it was reported that sustained systemic or intracerebroventricular IL-1b administration resulted in marked and persistent HPA activation, including protracted variations of CRH, CRH receptor mRNA expression, as well as elevated adrenocorticotropic hormone (ACTH), beta-endorphin and corticosterone secretion (60, 61). It was also reported, however, that although acute IFN-a treatment produced little effect, repeated IFN-a treatment led to reduced DA utilization (62) and increased low-affinity for 5-HT1A receptors sites (63). Other investigators reported that neither acute nor chronic IFN-a treatment appreciably influenced HPA functioning, and acute IFN-a did not affect monoamine turnover. In contrast, with sustained IFN-a over 14 days, DA levels were reduced in the PFC, 5-HT turnover was increased in the amygdala, and 5-HT levels were diminished (64). Finally, it was also reported that with repeated systemic injections or with continuous IL-1b infusion, the sickness and the plasma corticosterone elevations ordinarily elicited by acute IL-1b were diminished, whereas the central cytokine mRNA changes were sustained (1).
In effect, it seems that in response to cytokines there are elements subject to an adaptation-like effect, whereas for other actions the adaptation was less apparent. In fact, it appeared that although peripherally released cytokines returned to basal levels with continuous exposure to recombinant cytokines, brain cytokine alterations persisted (1). It may be that adaptive mechanisms exist within the periphery, thereby limiting the damaging effects of chronic cytokine elevation, but these processes may be diminished or lacking within the brain, and might thus favor the development of brain and behavioral pathologies.
3.3. Synergies associated with cytokine treatments
Beyond their individual effects, cytokine combinations (e.g., IL-1b plus IL-6, or IL-1b plus TNF-a) synergistically increased neuroendocrine functioning (30, 65-67), and it seems that cytokines and stressors may synergistically influence behavioral and neurochemical responses. In particular, it was shown that IL-1b and a stressor synergistically increased the in vivo release of hippocampal 5-HT (36, 38). Moreover, when a cytokine (IFN-a), viral analogue (polyinosinic:polycytidylic acid; poly I:C) or bacterial endotoxin treatment (lipopolysaccharide; LPS) was administered to mice that had experienced a psychosocial stressor, the behavioral, corticoid and monoamine alterations ordinarily elicited by the immune challenges were greatly increased (42, 68-70). As will be seen shortly, such findings have implications for the therapeutic use of cytokines.
3.4. Sensitization of cytokine-provoked neuronal processes
Stressor treatments result in the sensitization of neuronal processes, so that upon later re-exposure to such an insult brain monoamine changes are markedly increased. It likewise appears that cytokines may engender sensitized neurochemical functioning so that the HPA response to subsequent cytokine treatments may be enhanced. Interestingly, this response was not only evident when animals were re-exposed to the cytokine, but also when the later challenge involved a stressor (cross-sensitization) (32, 33, 71-73). Conversely, it was shown that the initial stressor exposure also augmented the corticoid response elicited by later LPS administration (74, 75). However, if rats were pretreated with the IL-1 antagonist, IL-1ra, then the effect of the subsequent stressor treatment was attenuated (76).
Beyond sensitized monoamine neuronal activity, cytokine treatments may engender sensitization of neuropeptide systems, such as CRH and AVP. Interestingly, the sensitization appears to become more pronounced with the passage of time. Specifically, in response to stressors, as well as to IL-1b and TNF-a. these treatments elicited progressively more pronounced and persistent elevations in the co-expression of AVP and CRH within CRH terminals located within the external zone of the median eminence. Typically, the co-expression of these peptides became apparent over several weeks following the cytokine treatment, and once evident, persisted for an extended period. Inasmuch as CRH and AVP synergistically stimulate ACTH secretion from the anterior pituitary, it was maintained that the phenotypic change within CRH neurons accounted for the greater effects of cytokines (and stressors) on HPA functioning. Given the persistence of these effects, it was suggested that stressor- and cytokine-elicited CRH-AVP co-expression might contribute to the depressive symptoms provoked in response to later stressor or cytokine challenges (33, 72, 73, 77).
Typically, studies assessing sensitized neuronal responses to stressors and cytokines have done so in adult animals. It is similarly possible that such processes might be operative in determining the protracted effects of these treatments applied early in life. In this regard, paralleling the effects of early life stressors, it has been shown that among rats pups that had been exposed to an endotoxin challenge during the early postnatal period, stressor challenges experienced in adulthood augmented stressor-elicited corticosterone reactivity, lymphocyte sensitivity to suppression by stressors, and protection against adjuvant-induced arthritis (78). At this time, it is uncertain whether the effects of early life stressors and early life cytokine treatments involve similar neural circuits. However, it is possible that epigenetic processes are involved in the response to cytokines as they might be with respect to early life experiences (79), thereby influencing adult responses to stressor and cytokine challenges.
4. BEHAVIORAL EFFECTS ASSOCIATED WITH CYTOKINES - ANIMAL STUDIES
4.1. Sickness behaviors
The release of pro-inflammatory cytokines, in response to inflammation, has been associated with a constellation of behavioral and physiological changes in animal models, collectively referred to as sickness behaviors. These include fever, sleep irregularities (e.g., somnolence, fatigue), anorexia, reduced motor activity (e.g., lethargy, apathy), as well as piloerection, ptosis and curled body posture (110). In addition to neurovegetative symptoms, inflammatory challenges also provoke psychosocial alterations, including diminished social interactions, coupled with cognitive and affective dysfunction, the latter characterized by disturbed operant performance and anhedonia (6, 18, 80). Although some of these effects are nonspecific and might reflect general malaise elicited by cytokine release, other symptoms may result from alterations of a centrally-mediated motivational state relevant to depression (1, 6).
Sickness behavior was initially described as a passive response reflecting the debilitating effects of an illness; however, it has also been characterized as an adaptive response geared towards recuperation (81). Many of the changes that occur during immune activation function to either minimize heat loss (i.e. the curled body position in animals), decrease energy expenditure (i.e. lethargy and reduced exploratory or social activity) or to produce the energy required to mount a febrile response (i.e. shivering). The febrile response is essential to recuperation as high core body temperatures stimulate the proliferation of immune cells necessary to combat the invasion, and concurrently slow the growth and proliferation of pathogens (81). In effect, the physiological and behavioral alterations, instead of reflecting general, nonspecific malaise engendered by cytokine release, may also be considered an organized strategy that is critical to the survival of the organism. Interestingly, the behavioral expression of sickness is contextually dependent in the sense that the signs of malaise are suppressed under conditions where sickness would be a disadvantage (e.g., in a novel or threatening environment; 82, 83), further emphasizing the view that sickness is a motivational state, rather than strictly a physiological one.
During an acute inflammatory reaction, several cytokines (IL-1b, TNF-a, and IL-6) are released as part of the organism's orchestrated immune response. Paralleling the neurochemical changes, behavioral alterations elicited by IL-1b are more pronounced than those of TNF-a, which are more pronounced than those of IL-6 (30) or those associated with IFN-a (42). These differential actions are evident irrespective of the route of administration (84). Aside from the direct effects of exogenous IL-1b administration, this cytokine also plays a significant role in the development of sickness behavior elicited by other cytokines, such as TNF-a, as well as a bacterial endotoxin and the viral imitator poly I:C (85). For instance, treatment with the antagonist, IL-1ra, not only diminishes the effects of IL-1b, but also inhibits the effects of LPS (86) and poly I:C (87). Additionally, compensatory mechanisms may exist should IL-1b be unavailable. For instance, IL-1b deficient mice demonstrated a typical response to an endotoxin challenge (85, 88), including the induction of sickness behavior, possibly by promoting increased release of TNF-a (85).
In addition to its involvement in cytokine-induced behavioral variations, IL-1b has also been implicated as a mediator in stressor-induced depressive-like behavior. For instance, it was reported that the behavioral and neuroendocrine effects of a chronic mild stressor were prevented among IL-1b type 1 receptor knockout mice (89). As well, mice lacking the IL-1b receptor also failed to display the usual reduction of neuroplasticity (hippocampal neurogenesis) that was evident in wild-type mice that received this stressor treatment (89). In contrast, genetic ablation of the TNF-a p55 receptor did not influence the HPA response provoked by restraint or LPS, although, as predicted, the corticoid elevation elicited by TNF-a was greatly attenuated (90). Hence, there is reason to suppose that selective IL-1b changes that foster the emergence depressive-like consequences might occur following exposure to certain stressors.
The sickness induced by TNF-a, it will be recalled, is less pronounced than that provoked by IL-1b. Importantly, however, in paradigms that have been associated with anhedonia (e.g., sucrose preference test) and motor disturbances (e.g., immobility in the forced swim test) that could reflect depression, mice lacking TNF-a receptors were more resilient than wild-type mice (91). Furthermore, mice with targeted deletion of TNF-a receptors displayed increased levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) within several brain regions, which could be associated with this resilience (92). Therefore, although the involvement of TNF-a in the emergence of sickness behavior may not be as integral as IL-1b, its role in the development of depressive-like behavior seems more significant.
In contrast to IL-1b and TNF-a, which peak early following an immune challenge and have relatively short half-lives, levels of IL-6 peak more gradually, and can remain in circulation for several hours (93). Studies using IL-6 deficient mice demonstrated that this cytokine might be fundamental in mediating LPS-induced immune activation (85, 94), but in general, the immediate behavioral effects of exogenously administered recombinant IL-6 are relatively subtle (30). It seems that despite its fever inducing actions (95, 96), the behavioral effects of IL-6 (such as reduced social exploration) are limited. Nonetheless, there has been progressively more attention focused on the involvement of this cytokine in mediating MDD (1). In fact, one recent report suggested that IL-6 might act directly within the hippocampus or amygdala to influence depressive-like behaviors and stressor-sensitive factors involved in neuroplasticity (97).
4.2. Depressive-like features elicited in response to pro-inflammatory factors
In addition to their sickness inducing effects, cytokines have also been reported to disrupt operant responding for food reward (98, 99) and markedly influence exploration and social interaction (100). However, these outcomes may be secondary effects of the treatments (e.g., general malaise) rather than variations of motivational or affective functioning. Unfortunately, it is often difficult to dissociate the sickness behavior elicited by cytokines from behaviors that may be related to depression.
Although sickness behavior has been thought to reflect human depressive symptoms, there are actually only a small number of studies that have attempted to dissociate symptoms linked to sickness from those of depression in animal models. There does, however, appear to be a difference in the time course between sickness emerging (within hours post-injection) and depression that appears as a second wave up to days post-injection (101, 102). For instance, although cytokine-induced motor retardation (a pivotal symptom of sickness) was attenuated 24 hours following an acute endotoxic challenge, decreased sucrose intake, and increased immobility in both the tail suspension and forced swim tests (paradigms thought to assess depressive-like behavior) persisted for several days, as did the increased c-fos expression in brain regions associated with depression, including the PVN, arcuate nucleus, and the amygdala (101). Similar results were found with more protracted immune activation, using chronic inoculation with Bacillus Calmette-Guerin, with sickness behavior becoming apparent almost immediately post-treatment and depressive-like symptoms emerging within several days and persisting up to several weeks with chronic treatment (102).
Consistent with the view that cytokines and bacterial endotoxins elicit a depressive-like state, it was shown that activation of the inflammatory immune system gives rise to anhedonia, a core symptom of depression. Specifically, endotoxin treatment disrupted responding for rewarding brain stimulation (31, 103-106). It is of particular significance that in the paradigm employed (i.e., assessing the response to a descending and then to an ascending series of currents), animals appeared to be fully capable of responding for rewarding stimulation. However, when the reward value was too low, those animals injected with LPS exhibited far greater reductions of responding relative to vehicle-treated animals. Thus, it seems that the effects of LPS likely reflected anhedonia (and thus depression) rather than motor decreases and malaise associated with sickness.
Paralleling these findings, it was shown that the anorexic and motivational (anhedonic) effects of cytokines (such as IL-1b) were distinguishable from one another. In fact, treatment with an antidepressant over 3 weeks primarily influenced the anhedonic effects of cytokines, without affecting sickness in general (106); see (107, 108). Specifically, IL-1b treatment markedly disrupted free-chow consumption as well as responding for sucrose reinforcement in rats performing on a progressive ratio (PR) schedule (i.e., a reward schedule in which a progressively greater number of operant responses are required for a fixed amount of sucrose, hence providing an index of the motivation to work for reward). Chronic antidepressant (fluoxetine) treatment attenuated the PR performance deficit for sucrose reward, but did not alter the diminished free-chow consumption provoked by the cytokine. Thus, the anhedonic and anorexic effects of cytokine treatment were dissociable, and antidepressant treatment preferentially influenced the motivational effects of IL-1b (anhedonia), and had little effect on the neurovegetative impact of the cytokine. As will be described in the ensuing sections, studies in humans have largely supported this perspective.
4.3. Processes governing cytokine-induced behavioral variations
The behavioral alterations provoked by the exogenous administration of pro-inflammatory cytokines (such as IL-1b, IL-6, and TNF-a) or bacterial endotoxins are thought to involve the central effects of peripherally released cytokines, as the impact of immune activation are attenuated by manipulations that influence brain cytokine functioning. For example, sickness behavior provoked by systemically administered LPS can be limited or precluded by the central administration of anti-inflammatory cytokines, such as IL-10, or cytokine receptor antagonists (e.g. IL-1ra; 100, 109).
Two distinct communication pathways might link peripheral inflammatory responses to CNS processing: a quick neural pathway and a slower humoral pathway (18). The former comprises a rapid wave that begins in the peritoneum where local immune cells secrete pro-inflammatory cytokines that activate vagal afferent fibers (6, 18, 65, 110). When these fibers are disrupted (by vagotomy) sickness behaviors induced by systemically administered IL-1b (111) and LPS (65) were attenuated. However, it was also posited that although vagal afferents are involved in relaying immune signals from the periphery to the CNS, other pathways are likely also involved.
Once the cytokine signals reach the CNS, the nucleus of the solitary tract (located in the brainstem) serves as a hub, relaying signals to other brain regions important in provoking the behavioral effects that accompany the inflammatory immune activation. Analysis of c-fos indicated that following activation of the vagus nerve and nucleus solitary tract, secondary projections of the vagus nerve, namely the parabrachial nucleus, PVN and supraoptic nuclei of the hypothalamus, the central and medial nuclei of the amygdala, and the bed nucleus of the stria terminalis may also be affected (112, 113).
The second communication pathway, which involves a humoral response, is a much slower process. As indicated earlier, peripheral cytokines gain access to the CNS via the circumventricular organs (CVOs) and choroid plexus, or enter the brain through an active transport mechanism (13), and then slowly diffuse by volume transmission into the brain parenchyma and to other brain targets such as the amygdaloid complex (18). The humoral pathway involves a series of second messenger molecules, including the prostaglandins, which diffuse into the brain and act on specialized receptors (namely EP3 and EP4) to innervate the brain regions involved in HPA activation and body temperature control, such as hypothalamic nuclei (18).
Recent attention has focused on the induction of cyclooxygenases (COX) in the mediation of the inflammatory immune response. The induction of COX activity leads to the synthesis of prostaglandins (by converting arachidonic acid into prostaglandin endoperoxide H2), which then provoke behavioral and neurochemical alterations (114). The two distinct COX subtypes, COX-1 and COX-2, share 60% homology (114). However, whereas COX-1 is ubiquitously expressed in most cell types and is responsible for maintaining normal physiological functioning, COX-2 is only expressed in certain cell types (e.g. endothelial cells), and is induced primarily by inflammatory stimuli (115). Considering its role in inflammation, most studies have focused on COX-2 receptors, and both LPS and IL-1b have been shown to increase its expression in brain endothelial cells (116). Furthermore, non-steroidal anti-inflammatory drugs (NSAIDs), which function by inhibiting COX expression, were found to attenuate LPS- and IL-1b-induced behavioral disturbances. Specifically, selective COX-2 inhibitors, such as indomethacin (117, 118) as well as nonselective inhibitors such as celecoxib (119), reduced the behavioral effects associated with an acute immune challenge. These results are supported by studies using COX knockout mice, where the behavioral effects of inflammation were reduced or absent following a challenge, although the distinct roles of both COX subtypes remain unclear (114). Taken together, it seems that although high levels of circulating cytokines provoke behavioral disturbances, their actions are at least partly dependent on the action of COX enzymes.
5. INFLAMMATORY FACTORS ASSOCIATED WITH DEPRESSION IN HUMANS
In addition to the sickness and depressive-like behaviors elicited by pro-inflammatory cytokines or bacterial endotoxins in animal models, converging evidence has also implicated activation of the inflammatory immune system in the promotion of human depressive symptoms. These findings come from studies in humans indicating that melancholic depression was associated with elevated circulating levels and mitogen-stimulated production of pro-inflammatory cytokines (4) and with increased concentrations of positive acute phase proteins (e.g., C-reactive protein; CRP; 120). In addition, it was found that the administration of inflammatory factors such as endotoxins promoted depressive-like symptoms (121) and that the prevalence of major depression was relatively high among patients with chronic inflammatory pathologies (8). Furthermore, IFN-a immunotherapy in the treatment of hepatitis C and certain cancers was associated with the development or the exacerbation of depressive symptoms and this outcome was reduced by antidepressant treatments (9).
5.1. Cytokine and acute phase protein correlates in patients with depressive disorders
Increased plasma/serum levels and production of several pro-inflammatory cytokines have been reported in patients with MDD (4). In this regard, elevations of IL-6 and of TNF-a were particularly notable in depressed individuals (122-130). Increased circulating levels of IL-1b also were found in MDD patients (4, 131, 132), although conflicting observations have been reported (130). Consistent with the view that peripheral cytokines are related to depression, treatment with antidepressants and mood stabilizers was associated with the normalization of IL-6 concentrations in depressed patients, but such an outcome was less apparent with respect to other cytokines (133). Moreover, depressed patients treated with antidepressant medication coupled with a COX-2 inhibitor displayed augmented effectiveness of the treatment (134), another illustration of the importance of inflammatory processes in subserving depression. Given the risk of gastrointestinal disturbances that may come about owing to sustained NSAID use, however, the usefulness of this combined treatment may be limited (135). Microglial activation, which is indicative of increased neuroinflammatory processes, was found within the dorsolateral PFC, anterior cingulate cortex, and mediodorsal thalamus of depressed, bipolar, and schizophrenic patients who committed suicide relative to patients who did not (136). However, there have been reports that depression was not associated with elevated circulating cytokine levels or with mitogen-stimulated cytokine production (1). In fact, higher production of IL-6 was reported in non-suicidal depressed patients than in patients who attempted suicide or normal controls (137).
Exaggerated activation of the inflammatory immune system also seemed to predict response to treatment in depressed patients. Higher serum levels of soluble receptor IL-2R and lower CC16 concentrations (a natural anti-inflammatory protein known to suppress IL-1b, IL-6, and IFN-gamma (IFN-g) secretion; 138) were observed in treatment non-responders (128). Similarly, particularly elevated production of IL-6 and of TNF-a was reported in depressed patients resistant to selective serotonin reuptake inhibitor (SSRI) and tricyclic treatment (127, 139), but not in former SSRI resistant patients who became euthymic (140). As well, anti-depressants decreased TNF-a production primarily in depressed patients who were treatment responders (127).
The varied cytokine irregularities reported in depressed individuals, coupled with differences in inflammatory states among patients who do or do not respond to antidepressant treatments, raises the possibility that cytokine variations may be related to the heterogeneity of symptoms or the severity of illness. Indeed, higher serum levels of IL-1b (141) and decreased production of IL-2, IFN-g, and IL-10 (142) were found in melancholic depressed patients compared to those with non-melancholic features. Other investigators, however, reported elevated production of IL-1b and of its receptor, IL-1ra, exclusively in non-melancholic patients (143). Likewise, increased IL-1b production was evident in patients with chronic mild depression (dysthymia), suggesting that illness chronicity was fundamental in promoting cytokine alterations (144).
Parenthetically, MDD has been increasingly documented as a risk factor for cardiovascular and cerebrovascular events (145). Given that elevated levels of the acute phase protein CRP was reported in depressed individuals (146-149) and in patients with cardiovascular diseases (149-152) the possibility was raised that this inflammatory marker might be the common denominator for the high comorbidity that exists between depressive and cardio- and cerebro-vascular disorders. In this regard, however, the role of CRP in mediating the association between depression and these vascular diseases was not consistently demonstrated (145, 153, 154) and thus, it seems that CRP may not systematically contribute to the relationship between depression and these vascular illnesses. Nevertheless, it is possible that CRP may be relevant for specific depression subtypes and/or for specific cardiovascular events. Unfortunately, unlike cytokines, differential patterns of CRP activation have not been reported in this regard.
5.2. Depressive symptoms in relation to allergies, chronic inflammatory diseases and cancer
A growing body of evidence has pointed to a link between allergies, depressive symptoms, and suicide. Mood worsening and a seasonal peak in suicide have been associated with high atmospheric pollen conditions and with peaks of seasonal allergen exposure (155-157). It was proposed that allergic inflammation might result from an abnormal activation of the Th2 cytokine system, such as IL-4, IL-5, and IL-13, which may influence brain functioning and potentially contribute to the development of depressive symptoms and, in some individuals, to suicide (158). Indeed, increased mRNA expression of Th2 cytokines was found in the orbitofrontal cortex (specifically Broadman 11 area) of suicide victims, and this outcome was moderated by gender, as IL-4 expression was elevated in women, whereas IL-13 expression was elevated in men (159). No differences, however, were reported for Th1 cytokines such as IL-1b, IL-6, TNF-a, and IL-5 in the same brain region (159). As discussed earlier, several Th1 cytokines, including TNF-a and IFN-a, have been implicated in depressive illness. Ultimately, it might be an imbalance in the ratio of Th1/ Th2 cytokines that negatively affects neurochemical activity in emotion regulatory brain regions.
In addition to the variations of depressive and suicide outcomes that occurred in association with allergic reactions, neuropsychiatric symptoms, including depression, were reported among patients suffering from pathological conditions involving chronic immune system alterations. This included individuals with chronic viral infections (e.g., hepatitis C), autoimmune inflammatory diseases such as rheumatoid arthritis, diabetes, and multiple sclerosis (MS), and some cancers (8). Although depressive manifestations in these patients may result from nonspecific factors, such a general malaise or psychological distress, there is also evidence that the comorbidity of these illnesses with depression may stem from the sustained activation of inflammatory processes.
For instance, non-medicated patients with chronic hepatitis C displayed higher plasma TNF-a levels than non-infected patients and this was coupled with an increase in the intensity of depressive manifestations (160). Interestingly, plasma cytokine levels in infected patients correlated significantly with three specific depressive symptoms clusters derived from the 21 items of the Beck Depression Inventory-II (161). Specifically, IL-1b correlated positively with negative cognitions (e.g., negative appraisal of self), whereas TNF-a correlated positively with negative cognitions, psychomotor-anhedonia (e.g., decreased satisfaction, loss of interest in people, psychomotor retardation or agitation) and vegetative symptoms (e.g., decreased appetite, insomnia; 160).
As in the case of hepatitis C, increased serum levels of TNF-a (128, 162, 163) were reported in non-medicated MS patients. Likewise, MS was associated with elevated mRNA expression of TNF-a, IFN-g, and IL-10 in whole blood cells and cerebrospinal fluid cells (164-166). Moreover, elevations in blood cytokine expression was more pronounced during an acute MS flare and this was correlated with depression scores (164). Further support for the contribution of inflammatory processes to the pathogenesis of MS-related depressive symptoms comes from imaging studies suggesting pre-existing signs of brain inflammation in MS patients influenced the progression of depressive symptoms (167).
Increased pro-inflammatory cytokine levels have been reported in cancer patients presenting with depressive symptoms. In this regard, depressed cancer patients displayed higher plasma concentrations of IL-6 than cancer patients without depression, or patients with major depression but without cancer (168, 169). Moreover, in advanced-stage cancer, depression and plasma IL-6 concentrations were found to be highly correlated (170). These data in themselves are obviously insufficient to warrant strong conclusions concerning the causal connection between IL-6 and depression. A case for IL-6 in mediating depression is somewhat strengthened by studies showing that IL-6 levels in depressed patients normalized with pharmacotherapy (133). Ultimately, however, it will be necessary to show that IL-6, in fact, might cause the emergence of depressive symptoms.
5.3. Depressive disorder induced by IFN-a activation
The data described earlier showing that certain cytokines and acute phase proteins were associated with major depression are simply correlational, hence precluding causal attributions concerning the inflammation-depression relationship. Stronger evidence supporting a causal role for cytokines in the provocation of MDD comes from the many studies showing that IFN-a immunotherapy (in the treatment of hepatitis C and some types of cancer) frequently provoked depressive symptoms, often necessitating discontinuation of the treatment (reviewed in 9). It ought to be underscored from the outset that patients in these studies were, no doubt, under considerable distress (given that they are suffering from life-threatening illnesses), and hence the outcomes may reflect the synergistic actions of the cytokines being administered on a stressor backdrop. Indeed, as described earlier in rodent studies, IFN-a had only modest (if any) behavioral effects, but marked behavioral and neurochemical alterations were apparent when the cytokine was administered in stressed animals (42).
Likewise, in line with the view that 5-HT changes associated with immunotherapy might contribute to depression, it was found that pre-existing biological markers (e.g., alterations of tryptophan, increased immune activation or elevated TNF-R1 and low IL-6R levels) predicted the development of depression during IFN-a therapy (171-173). Moreover, depression was most prominent among individuals that showed particularly marked tryptophan or cortisol elevations in response to the initial IFN-a administration (174, 175). As well, an association was observed between a specific polymorphism of the 5-HT1A receptor and the occurrence of depression during IFN-a treatment of chronic hepatitis C (176).
Despite its beneficial effects in the treatment of chronic hepatitis C and cancer, IFN-a therapy was associated with the development and/or exacerbation of depression as well as with a high incidence of nonspecific, neurovegetative symptoms such as fever, fatigue, lethargy, insomnia or hypersomnia, loss of appetite, malaise, anorexia, asthenia, myalgia, and social withdrawal (177-182). As described earlier, sickness behaviors associated with cytokine treatment in rodents have frequently been paralleled with human depressive/motivational symptoms of MDD. However, most of the features that comprise the sickness profile seem reminiscent of these neurovegetative symptoms of depression. In this regard, the reduced activity and increased sleep elicited by pro-inflammatory cytokines in rodents are characteristic of the neurovegetative features of atypical depression. In fact, pro-inflammatory cytokines are potent soporifics that increase slow wave sleep and reduce REM sleep, features that are aligned with atypical depression (183, 184). In contrast, the anorexia associated with cytokine or endotoxin treatment is more closely aligned with the typical form of depression (1). Thus, a given treatment, both in humans and in animal models, may instigate symptoms characteristic of both subtypes of depression, making it difficult to argue that a discrete set of neurovegetative (or motivational) features of depression are provoked by immune activation.
The depressive-like symptoms induced by IFN-a frequently resolved with treatment discontinuation or the use of antidepressants (185-187). Interestingly, antidepressants seemed more effective in attenuating symptoms such as depressed mood, anxiety, cognitive dysfunction, and pain, and were less efficacious for neurovegetative symptoms, such as fatigue, psychomotor slowing, altered sleep, or anorexia (see 9, 180). The latter symptoms correspond with the sickness behaviors characteristic of cytokine treatments in animal studies, and it was indeed reported in animal models that an SSRI was more effective in attenuating anhedonia than the anorexia elicited by a cytokine (106). Nevertheless, it has been reported that the initial neurovegetative effects elicited by IFN-a may be a marker for the subsequent development of depressive symptoms (58). Of course, this does not necessarily imply common mechanisms for the two sets of symptoms, but might simply be an index of those patients most reactive to the IFN-a.
The mechanisms by which IFN-a exerts its adverse behavioral effects are not yet fully understood. This cytokine is known to enhance the production of several pro-inflammatory cytokines, including IL-6 and TNF-a (188, 189). It was also reported that during IFN-a therapy in hepatitis C patients, the increased depressive symptoms were positively correlated with baseline or elevations of IL-2R, TNF-a and IL-6 concentrations (188, 190). This peripheral cytokine release may, in turn, affect central NE and 5-HT neurotransmission as well as HPA activity, which might thus promote MDD (191, 192). Indeed, severity of depressive symptoms (especially anorexia, pessimistic thoughts, suicidal ideations, and loss of concentration) after one month of IFN-a therapy was positively correlated with a decline of serum tryptophan concentrations (185).
As in the case of IFN-a immunotherapy, it was reported that IFN-b treatment in MS patients was also associated with confusion, depression, and anxiety. Unlike IFN-a, however, clinical reports of IFN-b-induced depressive features have been inconsistent (180). Depression and suicide attempts were more frequently reported during IFN-b therapy than during placebo administration (180, 193), yet several studies failed to show any evidence of increased depression or suicide in MS patients treated with IFN-b and in some instances, a decline of depression rates was even reported (194-196). It was suggested that depression in MS patients might not be a direct side effect of immunotherapy, but that pre-existing depressive episodes might favor the development of depressive symptoms during IFN-b treatment (197). It will be recalled that in hepatitis C and cancer patients treated with IFN-a, those individuals with premorbid depressive symptoms were also most likely to exhibit a depressive episode with the cytokine therapy. Thus, the inconsistent results reported concerning the actions of IFN-b may reflect basal differences in depressive characteristics that patients might have displayed.
5.4. Cognitive disturbances associated with cytokine (IFN) immunotherapy
In addition to the development of neurovegetative and depressive-like symptoms during IFN-a immunotherapy, this cytokine has been associated with the development and/or exacerbation of neuropsychiatric complications, including mania and anger/hostility symptoms, and with cognitive disturbances such as mnemonic problems and lack of concentration (180, 181, 198). Typically, within 6-8 hours of the initial administration IFN-a an acute influenza-like syndrome is apparent, including fever, chills, malaise, myalgias, arthralgias, and tachycardia, and symptoms gradually subside after about 2 weeks of treatment (192, 199). Sleep disturbances, irritability, weight loss, reduction of appetite, low mood, and cognitive dysfunction occurred later during IFN-a therapy, usually within about 1 to 3 months (57, 178). For instance, cognitive impairments, such as deficits in short term and working memory, as well as word fluency have been reported after 12 weeks of low-dose treatment with IFN-a (200). These cognitive dysfunctions associated with IFN-a were suggested to be indicative of prefrontal, temporo-cortical, and hippocampal alterations (200). Essentially, different brain systems may be affected during the course of IFN-a treatment, leading to diffuse symptoms. The early effects of the cytokine might occur within brain regions related to the neurovegetative symptoms, whereas other brain alterations (e.g., PFC, hippocampus) that follow, might be responsible for the cognitive impairments and depressive manifestations.
6. Inflammatory processes in relation to neuropsychiatric manifestations in pathological conditions other than depression
6.1. Confusional states and cognitive disturbances in relation to acute inflammation and surgical insult
Beyond the neurovegetative, depressive, and cognitive manifestations already described, delirium symptoms, such as deranged consciousness, confusional states, and other cognitive disturbances occur frequently in acutely ill or postoperatively patients among the elderly (201). Inflammatory processes were proposed as contributing to this syndrome by facilitating access of cytokines into the brain and increasing their damaging neuronal effects (202). Indeed, low premorbid circulating levels of the insulin growth factor (IGF-1) were found in acutely admitted elderly patients who developed delirium (203, 204). As IGF-1 has inhibitory effects on cytotoxic action of cytokines (205), it was suggested that low levels of this growth factor may favor brain susceptibility to the deleterious effects of cytokines (204).
Likewise, elevated circulating levels of chemokines (e.g., locally acting cytokines that enhance migration of inflammatory cells into the brain by weakening the BBB), but not of pro-inflammatory cytokines, were reported during the first 6h post-surgery in patients who developed delirium. The chemokine elevations were no longer detectable 4 days later, suggesting that they may play a role in the initial events associated with delirium (202). In contrast, pro-inflammatory cytokines and acute phase proteins may participate in the pathogenesis of delirium in later phases. In fact, elevated plasma levels of IL-6 were reported 24 to 48 hr after abdominal surgery in elderly patients who experienced post-operative confusion (206). Delirium incidence was also associated with increased levels of CRP 48 hours after stabilization from sepsis (207) and 48-60 hours after hip surgery in elderly patients (208, 209). Similarly, relative to cognitively normal patients, elderly patients with impaired mental status showed increased serum levels of IL-6, IL-8, and IL-10, four weeks after hip surgery, however, this outcome was independent of infectious, delirious, or cardiovascular complications (209). Contrary to cytokine and chemokine variations, CRP elevations after hip surgery were more prominent among patients with impaired mental status and infectious, delirious, or vascular complications (209).
6.2. Inflammation and cognitive decline in non-demented elderly and in demented patients
Recent evidence has suggested that inflammatory processes may also play a role in the normal age-related decline in cognitive functioning. Using the Edinburg Artery Study data base, elevated circulating IL-6 concentrations in non-demented older people were associated with a significantly steeper 4-year decline in general cognition and in nonverbal reasoning ability (210). Similar conclusions were found using the Rotterdam Study and the Leiden 85-plus Study data bases. Specifically, higher baseline levels of IL-6 were associated with worse cognitive functioning and more pronounced cognitive decline (211). Mild cognitive decline in elderly patients was also associated with higher levels of IFN-a and COX-2 relative to healthy elderly controls (212).
The purpose of the present review is not one of relating cytokines to cell loss and dementia. Nevertheless, there has been increasing data supporting the proposition that some of the manifestations associated with dementia (e.g., Alzheimer's disease) may involve inflammatory processes (reviewed in 1). For example, as reported in delirious patients, reduced serum concentrations of IGF-1 was observed in familial Alzheimer's disease (213), possibly predisposing the brain to inflammatory factors. Likewise, elevations of plasma IL-6, TNF-a and COX-2 levels were recently reported in Alzheimer patients relative to elderly individuals with mild cognitive impairments and to healthy elderly controls (212).
6.3. Immune activation and neuropsychiatric symptoms in schizophrenia
Although particular attention has been devoted to the analysis of cytokines in relation to major depressive illness and cognitive dysfunction, it is important to indicate that cytokines have also been implicated in other psychiatric disorders, in particular in schizophrenia. Indeed, activation of the inflammatory system was described in patients with schizophrenia and other psychotic disorders. Much like the correlates of MDD, higher concentrations and production of several cytokines (e.g., IL-6, IL-1R, IL-2, IL-8, IL-10, IFN- g, TNF-a, and lower levels of CC16 and of IL-4) were observed in schizophrenic patients (4, 214-218), although there have been contradictory reports in this regard (e.g., 219). Again, cytokine variations associated with schizophrenia were related to particular aspects of the disorder with elevated IL-2 levels being correlated to positive symptoms (220). Moreover, schizophrenia was associated with dysfunction related to the IL-3 gene in two population samples (221), and irregularities related to the IL-3 receptor were also reported (222). Interestingly, there have been reports of psychosis in hepatitis C patients during IFN-a therapy (223, 224). Admittedly, these reports have been infrequent, but together with the findings that circulating cytokines are elevated in schizophrenia, they support a role for inflammation in the pathogenesis of psychotic symptoms.
Normalization of cytokine elevations has been reported after antipsychotic medication in schizophrenic patients. For example, treatment with risperidone and haloperidol (atypical and typical antipsychotics, respectively) reduced IL-2 and IFN-g elevations, but failed to normalize IL-6 and IL-8 (225, 226). Risperidone also increased IL-2R and IL-10 levels and normalized CC16 concentrations (215, 225). Interestingly, as in depressed individuals, exaggerated activation of the inflammatory response also seemed to predict resistance to treatment in schizophrenic patients. Increased circulating levels of IL-6, IL-8, IL-10, IL-2, and IL-1ra (220, 227-229) were shown in treatment-refractory schizophrenics, but not in patients who responded to medication. Once more, however, other reports indicated that elevations of some cytokines were comparable among patients who were responders versus non-responders (219, 228). The differential effects of neuroleptic medication on schizophrenic symptoms, as well as on cytokine production, coupled with differential responsiveness to pharmacological treatments raises the possibility that different sub-classifications of schizophrenic symptoms (e.g. positive vs. negative) or subgroups of schizophrenia (e.g., paranoid vs. non paranoid) may be related to different cytokine (and neurotransmitter) activation profiles. Indeed, it has been reported that schizophrenic patients with elevated stimulated production of IFNs presented with more positive symptoms (e.g., delusions, hallucinations), whereas those with low IFN production showed more negative symptoms (e.g., social withdrawal, flat affect; 230).
Given that many of the same cytokines involved in MDD were also elevated in schizophrenia begs the question of how these same cytokine disturbances could be involved in these very different psychological disorders. One possibility is that the cytokine variations are a nonspecific index of disturbances being present. That is, inflammatory processes set the stage (acting as a vulnerability factor), but other hormonal and neurotransmitter changes come to promote the actual symptom profile presented. Alternatively, it could be that particular illnesses may be associated with a specific constellation of cytokine alterations, or that the effects of cytokines on pathology are largely determined by pre-existing vulnerabilities to particular pathological states.
7. SUMMARY AND PERSPECTIVE
Considerable evidence points to a role for inflammatory processes in MDD. These include correlational studies showing that (a) cytokine and acute phase protein levels are elevated among depressed individuals, (b) illnesses associated with immune activation are often comorbid with MDD, (c) cytokine treatments, such as IFN-a, give rise to a constellation of abnormal behaviors, including MDD, that can be attenuated by antidepressant medications, and (d) cytokines induce several neurochemical changes in animals, like those elicited by stressors, that have been implicated in MDD in humans. In both humans and animal models, the influence of inflammatory processes in provoking behavioral changes is particularly marked when applied on a stressor backdrop. Moreover, it also appears that activation of the inflammatory immune system may result in the sensitization of neuronal processes so that later stressor experiences are more apt to induce neurochemical changes that provoke MDD.
Together, clinical data on MDD, delirium, mild cognitive decline, and schizophrenia suggest that in otherwise apparently healthy patients, cytokine activation may exert little or no deleterious effects. However, under certain challenges (e.g., stressor background), or when neuronal damage is present, such as in patients suffering from chronic inflammatory pathologies, neurodegenerative dementia, or schizophrenia, in acutely ill or postoperative patients with brain inflammation, after IFN-a immunotherapy, or even as a result of normal aging of the brain, cytotoxic action of circulating cytokines may enhance neurodegenerative processes, thus leading to behavioral abnormalities (205).
Despite these multiple sources of support for a role for cytokines in mediating depressive illness, a fundamental caveat ought to be mentioned. Specifically, activation of the inflammatory immune system provokes a wide range of neurochemical and hormonal changes. Although some of these might contribute to MDD, others might result in neuronal loss leading to neurodegenerative disorders, or to toxicity that could promote a wide range of nonspecific symptoms (e.g., confusion, memory loss, delusions). Thus, it is possible that depression might be only one of many pathological outcomes that are promoted as result of widespread neuronal changes. This said, cytokines have been implicated in several pathological outcomes that involve CNS processes, and indeed, MDD is frequently comorbid with some neurodegenerative disorders as well as cardiovascular illness. It is possible, as previously suggested (1), that cytokines may represent a common denominator for these pathologies, and may be responsible for their comorbidity.
8. Acknowledgment
This work was supported by the Canadian Institutes of Health Research. Hymie Anisman and Shawn Hayley are Canada Research Chairs in Behavioral Neuroscience and in Neuroscience respectively. Marie Claude Audet is supported by a fellowship from the Fonds de la recherche en santé du Quebec (FRSQ).
9. REFERENCES
1. Anisman H., Z. Merali, S. Hayley: Neurotransmitter, peptide and cytokine processes in relation to depressive disorder: comorbidity between depression and neurodegenerative disorders. Prog Neurobiol 85, 1-74 (2008)
doi:10.1016/j.pneurobio.2008.01.004
2. Duman R.S., L.M. Monteggia: A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59, 1116-1127 (2006)
doi:10.1016/j.biopsych.2006.02.013
3. Anisman H., K. Matheson: Stress, depression, and anhedonia: caveats concerning animal models. Neurosci Biobehav Rev 29, 525-546 (2005)
doi:10.1016/j.neubiorev.2005.03.007
4. Maes M.: Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 19, 11-38 (1995)
doi:10.1016/0278-5846(94)00101-M
5. Maes M.: Major depression and activation of the inflammatory response system. Adv Exp Med Biol 461, 25-46 (1999)
doi:10.1007/978-0-585-37970-8_2
6. Dantzer R., J.C. O'Connor, G.G. Freund, R.W. Johnson, K.W. Kelley: From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9, 46-56 (2008)
doi:10.1038/nrn2297
7. Hayley S., H. Anisman: Multiple mechanisms of cytokine action in neurodegenerative and psychiatric states: neurochemical and molecular substrates. Curr Pharm Des 11, 947-962 (2005)
doi:10.2174/1381612053381611
8. Yirmiya R.: Depression in medical illness: the role of the immune system. West J Med 173, 333-336 (2000)
doi:10.1136/ewjm.173.5.333
9. Raison C.L., L. Capuron, A.H. Miller: Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 27, 24-31 (2006)
doi:10.1016/j.it.2005.11.006
10. Herman J.P., W.E. Cullinan: Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 20, 78-84 (1997)
doi:10.1016/S0166-2236(96)10069-2
11. Alkharfy K.M., J.A. Kellum, G.R. Matzke: Unintended immunomodulation: part I. Effects of common clinical conditions on cytokine biosynthesis. Shock 13, 333-345 (2000)
12. Oberholzer A., S.M. Souza, S.K. Tschoeke, C. Oberholzer, A. Abouhamze, J.P. Pribble, L.L. Moldawer: Plasma cytokine measurements augment prognostic scores as indicators of outcome in patients with severe sepsis. Shock 23, 488-493 (2005)
13. Banks W.A., S. Dohgu, J.L. Lynch, M.A. Fleegal-DeMotta, M.A. Erickson, R. Nakaoke, T.Q. Vo: Nitric oxide isoenzymes regulate lipopolysaccharide-enhanced insulin transport across the blood-brain barrier. Endocrinology 149, 1514-1523 (2008)
doi:10.1210/en.2007-1091
14. Banks W.A., A.J. Kastin: Blood to brain transport of interleukin links the immune and central nervous systems. Life Sci 48, PL117-121 (1991)
doi:10.1016/0024-3205(91)90385-O
15. Saija A., P. Princi, M. Lanza, M. Scalese, E. Aramnejad, A. De Sarro: Systemic cytokine administration can affect blood-brain barrier permeability in the rat. Life Sci 56, 775-784 (1995)
doi:10.1016/0024-3205(95)00008-T
16. de Vries H.E., M.C. Blom-Roosemalen, M. van Oosten, A.G. de Boer, T.J. van Berkel, D.D. Breimer, J. Kuiper: The influence of cytokines on the integrity of the blood-brain barrier in vitro. J Neuroimmunol 64, 37-43 (1996)
doi:10.1016/0165-5728(95)00148-4
17. Rivest S., S. Lacroix, L. Vallieres, S. Nadeau, J. Zhang, N. Laflamme: How the blood talks to the brain parenchyma and the paraventricular nucleus of the hypothalamus during systemic inflammatory and infectious stimuli. Proc Soc Exp Biol Med 223, 22-38 (2000)
doi:10.1046/j.1525-1373.2000.22304.x
18. Konsman J.P., P. Parnet, R. Dantzer: Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci 25, 154-159 (2002)
doi:10.1016/S0166-2236(00)02088-9
19. Nadeau S., S. Rivest: Effects of circulating tumor necrosis factor on the neuronal activity and expression of the genes encoding the tumor necrosis factor receptors (p55 and p75) in the rat brain: a view from the blood-brain barrier. Neuroscience 93, 1449-1464 (1999)
doi:10.1016/S0306-4522(99)00225-0
20. Johnson A.B., S. Bake, D.K. Lewis, F. Sohrabji: Temporal expression of IL-1beta protein and mRNA in the brain after systemic LPS injection is affected by age and estrogen. J Neuroimmunol 174, 82-91 (2006)
doi:10.1016/j.jneuroim.2006.01.019
21. Kamm K., W. Vanderkolk, C. Lawrence, M. Jonker, A.T. Davis: The effect of traumatic brain injury upon the concentration and expression of interleukin-1beta and interleukin-10 in the rat. J Trauma 60, 152-157 (2006)
doi:10.1097/01.ta.0000196345.81169.a1
22. Zhu Y., K. Saito, Y. Murakami, M. Asano, Y. Iwakura, M. Seishima: Early increase in mRNA levels of pro-inflammatory cytokines and their interactions in the mouse hippocampus after transient global ischemia. Neurosci Lett 393, 122-126 (2006)
doi:10.1016/j.neulet.2005.08.072
23. Churchill L., P. Taishi, M. Wang, J. Brandt, C. Cearley, A. Rehman, J.M. Krueger: Brain distribution of cytokine mRNA induced by systemic administration of interleukin-1beta or tumor necrosis factor alpha. Brain Res 1120, 64-73 (2006)
doi:10.1016/j.brainres.2006.08.083
24. Ledeboer A., R. Binnekade, J.J. Breve, J.G. Bol, F.J. Tilders, A.M. Van Dam: Site-specific modulation of LPS-induced fever and interleukin-1 beta expression in rats by interleukin-10. Am J Physiol Regul Integr Comp Physiol 282, R1762-1772 (2002)
25. Rivest S.: How circulating cytokines trigger the neural circuits that control the hypothalamic-pituitary-adrenal axis. Psychoneuroendocrinology 26, 761-788 (2001)
doi:10.1016/S0306-4530(01)00064-6
26. Sriram K., J.M. Matheson, S.A. Benkovic, D.B. Miller, M.I. Luster, J.P. O'Callaghan: Deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP-induced neurotoxicity: role of TNF-alpha. FASEB J 20, 670-682 (2006)
doi:10.1096/fj.05-5106com
27. Maier S.F., K.T. Nguyen, T. Deak, E.D. Milligan, L.R. Watkins: Stress, learned helplessness, and brain interleukin-1 beta. Adv Exp Med Biol 461, 235-249 (1999)
doi:10.1007/978-0-585-37970-8_13
28. Miyahara S., T. Komori, R. Fujiwara, K. Shizuya, M. Yamamoto, M. Ohmori, Y. Okazaki: Effects of repeated stress on expression of interleukin-6 (IL-6) and IL-6 receptor mRNAs in rat hypothalamus and midbrain. Life Sci 66, PL93-98 (2000)
doi:10.1016/S0024-3205(99)00626-8
29. Nguyen K.T., T. Deak, S.M. Owens, T. Kohno, M. Fleshner, L.R. Watkins, S.F. Maier: Exposure to acute stress induces brain interleukin-1beta protein in the rat. J Neurosci 18, 2239-2246 (1998)
30. Brebner K., S. Hayley, R. Zacharko, Z. Merali, H. Anisman: Synergistic effects of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha: central monoamine, corticosterone, and behavioral variations. Neuropsychopharmacology 22, 566-580 (2000)
doi:10.1016/S0893-133X(99)00166-9
31. Anisman H., Z. Merali: Anhedonic and anxiogenic effects of cytokine exposure. Adv Exp Med Biol 461, 199-233 (1999)
doi:10.1007/978-0-585-37970-8_12
32. Hayley S., K. Brebner, S. Lacosta, Z. Merali, H. Anisman: Sensitization to the effects of tumor necrosis factor-alpha: neuroendocrine, central monoamine, and behavioral variations. J Neurosci 19, 5654-5665 (1999)
33. Hayley S., P. Wall, H. Anisman: Sensitization to the neuroendocrine, central monoamine and behavioural effects of murine tumor necrosis factor-alpha: peripheral and central mechanisms. Eur J Neurosci 15, 1061-1076 (2002)
doi:10.1046/j.1460-9568.2002.01936.x
34. Day H.E., E.J. Curran, S.J. Watson, Jr., H. Akil: Distinct neurochemical populations in the rat central nucleus of the amygdala and bed nucleus of the stria terminalis: evidence for their selective activation by interleukin-1beta. J Comp Neurol 413, 113-128 (1999)
doi:10.1002/(SICI)1096-9861(19991011)413:1<113::AID-CNE8>3.0.CO;2-B
35. Linthorst A.C., C. Flachskamm, P. Muller-Preuss, F. Holsboer, J.M. Reul: Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study. J Neurosci 15, 2920-2934 (1995)
36. Merali Z., S. Lacosta, H. Anisman: Effects of interleukin-1beta and mild stress on alterations of norepinephrine, dopamine and serotonin neurotransmission: a regional microdialysis study. Brain Res 761, 225-235 (1997)
doi:10.1016/S0006-8993(97)00312-0
37. Shintani F., S. Kanba, T. Nakaki, M. Nibuya, N. Kinoshita, E. Suzuki, G. Yagi, R. Kato, M. Asai: Interleukin-1 beta augments release of norepinephrine, dopamine, and serotonin in the rat anterior hypothalamus. J Neurosci 13, 3574-3581 (1993)
38. Song C., Z. Merali, H. Anisman: Variations of nucleus accumbens dopamine and serotonin following systemic interleukin-1, interleukin-2 or interleukin-6 treatment. Neuroscience 88, 823-836 (1999)
doi:10.1016/S0306-4522(98)00271-1
39. Zhang J., L. Terreni, M.G. De Simoni, A.J. Dunn: Peripheral interleukin-6 administration increases extracellular concentrations of serotonin and the evoked release of serotonin in the rat striatum. Neurochem Int 38, 303-308 (2001)
doi:10.1016/S0197-0186(00)00099-1
40. Schaefer M., M. Schwaiger, M. Pich, K. Lieb, A. Heinz: Neurotransmitter changes by interferon-alpha and therapeutic implications. Pharmacopsychiatry 36 Suppl 3, S203-206 (2003)
doi:10.1055/s-2003-45131
41. Anisman H., J. Gibb, S. Hayley: Influence of continuous infusion of interleukin-1beta on depression-related processes in mice: corticosterone, circulating cytokines, brain monoamines, and cytokine mRNA expression. Psychopharmacology (Berl) 199, 231-244 (2008)
doi:10.1007/s00213-008-1166-z
42. Anisman H., M.O. Poulter, R. Gandhi, Z. Merali, S. Hayley: Interferon-alpha effects are exaggerated when administered on a psychosocial stressor backdrop: cytokine, corticosterone and brain monoamine variations. J Neuroimmunol 186, 45-53 (2007)
doi:10.1016/j.jneuroim.2007.02.008
43. Cassidy E.M., D. Manning, S. Byrne, E. Bolger, F. Murray, N. Sharifi, E. Wallace, M. Keogan, V. O'Keane: Acute effects of low-dose interferon-alpha on serum cortisol and plasma interleukin-6. J Psychopharmacol 16, 230-234 (2002)
44. Shimizu H., K. Ohtani, N. Sato, T. Nagamine, M. Mori: Increase in serum interleukin-6, plasma ACTH and serum cortisol levels after systemic interferon-alpha administration. Endocr J 42, 551-556 (1995)
doi:10.1507/endocrj.42.551
45. Gisslinger H., T. Svoboda, M. Clodi, B. Gilly, H. Ludwig, L. Havelec, A. Luger: Interferon-alpha stimulates the hypothalamic-pituitary-adrenal axis in vivo and in vitro. Neuroendocrinology 57, 489-495 (1993)
doi:10.1159/000126396
46. Kitagami T., K. Yamada, H. Miura, R. Hashimoto, T. Nabeshima, T. Ohta: Mechanism of systemically injected interferon-alpha impeding monoamine biosynthesis in rats: role of nitric oxide as a signal crossing the blood-brain barrier. Brain Res 978, 104-114 (2003)
doi:10.1016/S0006-8993(03)02776-8
47. Yokoyama M., E. Suzuki, T. Sato, S. Maruta, K. Inada, S. Watanabe, H. Miyaoka: Effects of intraperitoneal administration of IFN-alpha for one, four, and fourteen days on amino acid levels in various rat brain regions. J Interferon Cytokine Res 25, 187-191 (2005)
doi:10.1089/jir.2005.25.187
48. Raber J., G.F. Koob, F.E. Bloom: Interferon-alpha and transforming growth factor-beta 1 regulate corticotropin-releasing factor release from the amygdala: comparison with the hypothalamic response. Neurochem Int 30, 455-463 (1997)
doi:10.1016/S0197-0186(96)00082-4
49. Hori T., T. Katafuchi, S. Take, N. Shimizu: Neuroimmunomodulatory actions of hypothalamic interferon-alpha. Neuroimmunomodulation 5, 172-177 (1998)
doi:10.1159/000026334
50. De La Garza R., 2nd, G.M. Asnis: The non-steroidal anti-inflammatory drug diclofenac sodium attenuates IFN-alpha induced alterations to monoamine turnover in prefrontal cortex and hippocampus. Brain Res 977, 70-79 (2003)
doi:10.1016/S0006-8993(03)02757-4
51. Morikawa O., N. Sakai, H. Obara, N. Saito: Effects of interferon-alpha, interferon-gamma and cAMP on the transcriptional regulation of the serotonin transporter. Eur J Pharmacol 349, 317-324 (1998)
doi:10.1016/S0014-2999(98)00187-3
52. Yang W., Q. Wang, S.J. Kanes, J.M. Murray, K. Nishikura: Altered RNA editing of serotonin 5-HT2C receptor induced by interferon: implications for depression associated with cytokine therapy. Brain Res Mol Brain Res 124, 70-78 (2004)
doi:10.1016/j.molbrainres.2004.02.010
53. Merali Z., T. Bedard, N. Andrews, B. Davis, A.T. McKnight, M.I. Gonzalez, M. Pritchard, P. Kent, H. Anisman: Bombesin receptors as a novel anti-anxiety therapeutic target: BB1 receptor actions on anxiety through alterations of serotonin activity. J Neurosci 26, 10387-10396 (2006)
doi:10.1523/JNEUROSCI.1219-06.2006
54. Gurevich I., H. Tamir, V. Arango, A.J. Dwork, J.J. Mann, C. Schmauss: Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron 34, 349-356 (2002)
doi:10.1016/S0896-6273(02)00660-8
55. Schmauss C.: Serotonin 2C receptors: suicide, serotonin, and runaway RNA editing. Neuroscientist 9, 237-242 (2003)
doi:10.1177/1073858403253669
56. Menkes D.B., J.A. MacDonald: Interferons, serotonin and neurotoxicity. Psychol Med 30, 259-268 (2000)
doi:10.1017/S0033291799001774
57. Capuron L., J.F. Gumnick, D.L. Musselman, D.H. Lawson, A. Reemsnyder, C.B. Nemeroff, A.H. Miller: Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology 26, 643-652 (2002)
doi:10.1016/S0893-133X(01)00407-9
58. Wichers M.C., G.H. Koek, G. Robaeys, A.J. Praamstra, M. Maes: Early increase in vegetative symptoms predicts IFN-alpha-induced cognitive-depressive changes. Psychol Med 35, 433-441 (2005)
doi:10.1017/S0033291704003526
59. Wichers M.C., M. Maes: The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. J Psychiatry Neurosci 29, 11-17 (2004)
60. Parsadaniantz S.M., A. Lebeau, P. Duval, B. Grimaldi, B. Terlain, B. Kerdelhue: Effects of the inhibition of cyclo-oxygenase 1 or 2 or 5-lipoxygenase on the activation of the hypothalamic-pituitary-adrenal axis induced by interleukin-1beta in the male Rat. J Neuroendocrinol 12, 766-773 (2000)
doi:10.1046/j.1365-2826.2000.00517.x
61. van der Meer M.J., C.G. Sweep, G.J. Pesman, F.J. Tilders, A.R. Hermus: Chronic stimulation of the hypothalamus-pituitary-adrenal axis in rats by interleukin 1beta: central and peripheral mechanisms. Cytokine 8, 910-919 (1996)
doi:10.1006/cyto.1996.0122
62. Shuto H., Y. Kataoka, T. Horikawa, N. Fujihara, R. Oishi: Repeated interferon-alpha administration inhibits dopaminergic neural activity in the mouse brain. Brain Res 747, 348-351 (1997)
doi:10.1016/S0006-8993(96)01371-6
63. Abe S., T. Hori, T. Suzuki, A. Baba, H. Shiraishi, T. Yamamoto: Effects of chronic administration of interferon alpha A/D on serotonergic receptors in rat brain. Neurochem Res 24, 359-363 (1999)
doi:10.1023/A:1020929415443
64. De La Garza R., 2nd, G.M. Asnis, E. Pedrosa, C. Stearns, A.L. Migdal, J.F. Reinus, R. Paladugu, S. Vemulapalli: Recombinant human interferon-alpha does not alter reward behavior, or neuroimmune and neuroendocrine activation in rats. Prog Neuropsychopharmacol Biol Psychiatry 29, 781-792 (2005)
doi:10.1016/j.pnpbp.2005.03.008
65. Bluthe R.M., V. Walter, P. Parnet, S. Laye, J. Lestage, D. Verrier, S. Poole, B.E. Stenning, K.W. Kelley, R. Dantzer: Lipopolysaccharide induces sickness behaviour in rats by a vagal mediated mechanism. C R Acad Sci III 317, 499-503 (1994)
No DOI Found
66. Zhou D., N. Shanks, S.E. Riechman, R. Liang, A.W. Kusnecov, B.S. Rabin: Interleukin 6 modulates interleukin-1-and stress-induced activation of the hypothalamic-pituitary-adrenal axis in male rats. Neuroendocrinology 63, 227-236 (1996)
doi:10.1159/000126962
67. Van der Meer M.J., C.G. Sweep, G.J. Pesman, G.F. Borm, A.R. Hermus: Synergism between IL-1 beta and TNF-alpha on the activity of the pituitary-adrenal axis and on food intake of rats. Am J Physiol 268, E551-557 (1995)
68. Gandhi R., S. Hayley, J. Gibb, Z. Merali, H. Anisman: Influence of poly I:C on sickness behaviors, plasma cytokines, corticosterone and central monoamine activity: moderation by social stressors. Brain Behav Immun 21, 477-489 (2007)
doi:10.1016/j.bbi.2006.12.005
69. Gibb J., S. Hayley, R. Gandhi, M.O. Poulter, H. Anisman: Synergistic and additive actions of a psychosocial stressor and endotoxin challenge: Circulating and brain cytokines, plasma corticosterone and behavioral changes in mice. Brain Behav Immun 22, 573-589 (2008)
doi:10.1016/j.bbi.2007.12.001
70. Quan N., R. Avitsur, J.L. Stark, L. He, W. Lai, F. Dhabhar, J.F. Sheridan: Molecular mechanisms of glucocorticoid resistance in splenocytes of socially stressed male mice. J Neuroimmunol 137, 51-58 (2003)
doi:10.1016/S0165-5728(03)00042-0
71. Anisman H., Z. Merali, S. Hayley: Sensitization associated with stressors and cytokine treatments. Brain Behav Immun 17, 86-93 (2003)
doi:10.1016/S0889-1591(02)00100-9
72. Hayley S., S. Lacosta, Z. Merali, N. van Rooijen, H. Anisman: Central monoamine and plasma corticosterone changes induced by a bacterial endotoxin: sensitization and cross-sensitization effects. Eur J Neurosci 13, 1155-1165 (2001) doi:10.1046/j.0953-816x.2001.01496.x
73. Schmidt E.D., A.W. Janszen, F.G. Wouterlood, F.J. Tilders: Interleukin-1-induced long-lasting changes in hypothalamic corticotropin-releasing hormone (CRH)--neurons and hyperresponsiveness of the hypothalamus-pituitary-adrenal axis. J Neurosci 15, 7417-7426 (1995)
74. Johnson J.D., K.A. O'Connor, T. Deak, M. Stark, L.R. Watkins, S.F. Maier: Prior stressor exposure sensitizes LPS-induced cytokine production. Brain Behav Immun 16, 461-476 (2002)
doi:10.1006/brbi.2001.0638
75. Johnson J.D., K.A. O'Connor, M.K. Hansen, L.R. Watkins, S.F. Maier: Effects of prior stress on LPS-induced cytokine and sickness responses. Am J Physiol Regul Integr Comp Physiol 284, R422-432 (2003)
76. Johnson J.D., K.A. O'Connor, L.R. Watkins, S.F. Maier: The role of IL-1beta in stress-induced sensitization of proinflammatory cytokine and corticosterone responses. Neuroscience 127, 569-577 (2004)
doi:10.1016/j.neuroscience.2004.05.046
77. Tilders F.J., E.D. Schmidt: Cross-sensitization between immune and non-immune stressors. A role in the etiology of depression? Adv Exp Med Biol 461, 179-197 (1999)
doi:10.1007/978-0-585-37970-8_11
78. Shanks N., R.J. Windle, P.A. Perks, M.S. Harbuz, D.S. Jessop, C.D. Ingram, S.L. Lightman: Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation. Proc Natl Acad Sci U S A 97, 5645-5650 (2000)
doi:10.1073/pnas.090571897
79. Weaver I.C., N. Cervoni, F.A. Champagne, A.C. D'Alessio, S. Sharma, J.R. Seckl, S. Dymov, M. Szyf, M.J. Meaney: Epigenetic programming by maternal behavior. Nat Neurosci 7, 847-854 (2004)
doi:10.1038/nn1276
80. Yirmiya R., Y. Pollak, M. Morag, A. Reichenberg, O. Barak, R. Avitsur, Y. Shavit, H. Ovadia, J. Weidenfeld, A. Morag, M.E. Newman, T. Pollmacher: Illness, cytokines, and depression. Ann N Y Acad Sci 917, 478-487 (2000)
81. Dantzer R.: Cytokine-induced sickness behavior: mechanisms and implications. Ann N Y Acad Sci 933, 222-234 (2001)
82. Kusnecov A.W., R. Liang, G. Shurin: T-lymphocyte activation increases hypothalamic and amygdaloid expression of CRH mRNA and emotional reactivity to novelty. J Neurosci 19, 4533-4543 (1999)
83. Cohn D.W., L.C. de Sa-Rocha: Differential effects of lipopolysaccharide in the social behavior of dominant and submissive mice. Physiol Behav 87, 932-937 (2006)
doi:10.1016/j.physbeh.2006.02.011
84. Quan N., M. Herkenham: Connecting cytokines and brain: a review of current issues. Histol Histopathol 17, 273-288 (2002)
85. Bluthe R.M., S. Laye, B. Michaud, C. Combe, R. Dantzer, P. Parnet: Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice. Eur J Neurosci 12, 4447-4456 (2000)
doi:10.1046/j.1460-9568.2000.01348.x
86. Bluthe R.M., R. Dantzer, K.W. Kelley: Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat. Brain Res 573, 318-320 (1992)
doi:10.1016/0006-8993(92)90779-9
87. Fortier M.E., S. Kent, H. Ashdown, S. Poole, P. Boksa, G.N. Luheshi: The viral mimic, polyinosinic:polycytidylic acid, induces fever in rats via an interleukin-1-dependent mechanism. Am J Physiol Regul Integr Comp Physiol 287, R759-766 (2004)
doi:10.1152/ajpregu.00293.2004
88. Fantuzzi G., H. Zheng, R. Faggioni, F. Benigni, P. Ghezzi, J.D. Sipe, A.R. Shaw, C.A. Dinarello: Effect of endotoxin in IL-1 beta-deficient mice. J Immunol 157, 291-296 (1996)
89. Goshen I., T. Kreisel, H. Ounallah-Saad, P. Renbaum, Y. Zalzstein, T. Ben-Hur, E. Levy-Lahad, R. Yirmiya: A dual role for interleukin-1 in hippocampal-dependent memory processes. Psychoneuroendocrinology 32, 1106-1115 (2007)
doi:10.1016/j.psyneuen.2007.09.004
90. Hayley S., O. Kelly, H. Anisman: Corticosterone changes in response to stressors, acute and protracted actions of tumor necrosis factor-alpha, and lipopolysaccharide treatments in mice lacking the tumor necrosis factor-alpha p55 receptor gene. Neuroimmunomodulation 11, 241-246 (2004)
doi:10.1159/000078442
91. Simen B.B., C.H. Duman, A.A. Simen, R.S. Duman: TNFalpha signaling in depression and anxiety: behavioral consequences of individual receptor targeting. Biol Psychiatry 59, 775-785 (2006)
doi:10.1016/j.biopsych.2005.10.013
92. Yamada K., R. Iida, Y. Miyamoto, K. Saito, K. Sekikawa, M. Seishima, T. Nabeshima: Neurobehavioral alterations in mice with a targeted deletion of the tumor necrosis factor-alpha gene: implications for emotional behavior. J Neuroimmunol 111, 131-138 (2000)
doi:10.1016/S0165-5728(00)00375-1
93. Kemna E., P. Pickkers, E. Nemeth, H. van der Hoeven, D. Swinkels: Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 106, 1864-1866 (2005)
doi:10.1182/blood-2005-03-1159
94. Harden L.M., I. du Plessis, S. Poole, H.P. Laburn: Interleukin-6 and leptin mediate lipopolysaccharide-induced fever and sickness behavior. Physiol Behav 89, 146-155 (2006)
doi:10.1016/j.physbeh.2006.05.016
95. Cartmell T., S. Poole, A.V. Turnbull, N.J. Rothwell, G.N. Luheshi: Circulating interleukin-6 mediates the febrile response to localised inflammation in rats. J Physiol 526 Pt 3, 653-661 (2000)
doi:10.1111/j.1469-7793.2000.00653.x
96. Lenczowski M.J., R.M. Bluthe, J. Roth, G.S. Rees, D.A. Rushforth, A.M. van Dam, F.J. Tilders, R. Dantzer, N.J. Rothwell, G.N. Luheshi: Central administration of rat IL-6 induces HPA activation and fever but not sickness behavior in rats. Am J Physiol 276, R652-658 (1999)
97. Wu T.H., C.H. Lin: IL-6 mediated alterations on immobile behavior of rats in the forced swim test via ERK1/2 activation in specific brain regions. Behav Brain Res (2008)
98. Bret-Dibat J.L., R.M. Bluthe, S. Kent, K.W. Kelley, R. Dantzer: Lipopolysaccharide and interleukin-1 depress food-motivated behavior in mice by a vagal-mediated mechanism. Brain Behav Immun 9, 242-246 (1995)
doi:10.1006/brbi.1995.1023
99. Kent S., J.L. Bret-Dibat, K.W. Kelley, R. Dantzer: Mechanisms of sickness-induced decreases in food-motivated behavior. Neurosci Biobehav Rev 20, 171-175 (1996)
doi:10.1016/0149-7634(95)00037-F
100. Bluthe R.M., R. Dantzer, K.W. Kelley: Central mediation of the effects of interleukin-1 on social exploration and body weight in mice. Psychoneuroendocrinology 22, 1-11 (1997)
doi:10.1016/S0306-4530(96)00042-X
101. Frenois F., M. Moreau, J. O'Connor, M. Lawson, C. Micon, J. Lestage, K.W. Kelley, R. Dantzer, N. Castanon: Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 32, 516-531 (2007)
doi:10.1016/j.psyneuen.2007.03.005
102. Moreau M., C. Andre, J.C. O'Connor, S.A. Dumich, J.A. Woods, K.W. Kelley, R. Dantzer, J. Lestage, N. Castanon: Inoculation of Bacillus Calmette-Guerin to mice induces an acute episode of sickness behavior followed by chronic depressive-like behavior. Brain Behav Immun 22, 1087-1095 (2008)
doi:10.1016/j.bbi.2008.04.001
103. Borowski T., L. Kokkinidis, Z. Merali, H. Anisman: Lipopolysaccharide, central in vivo biogenic amine variations, and anhedonia. Neuroreport 9, 3797-3802 (1998)
doi:10.1097/00001756-199812010-00006
104. Anisman H., L. Kokkinidis, T. Borowski, Z. Merali: Differential effects of interleukin (IL)-1beta, IL-2 and IL-6 on responding for rewarding lateral hypothalamic stimulation. Brain Res 779, 177-187 (1998)
doi:10.1016/S0006-8993(97)01114-1
105. Anisman H., L. Kokkinidis, Z. Merali: Further evidence for the depressive effects of cytokines: anhedonia and neurochemical changes. Brain Behav Immun 16, 544-556 (2002)
doi:10.1016/S0889-1591(02)00011-9
106. Merali Z., K. Brennan, P. Brau, H. Anisman: Dissociating anorexia and anhedonia elicited by interleukin-1beta: antidepressant and gender effects on responding for "free chow" and "earned" sucrose intake. Psychopharmacology (Berl) 165, 413-418 (2003)
107. Sammut S., I. Bethus, G. Goodall, R. Muscat: Antidepressant reversal of interferon-alpha-induced anhedonia. Physiol Behav 75, 765-772 (2002)
doi:10.1016/S0031-9384(02)00677-7
108. Sammut S., G. Goodall, R. Muscat: Acute interferon-alpha administration modulates sucrose consumption in the rat. Psychoneuroendocrinology 26, 261-272 (2001)
doi:10.1016/S0306-4530(00)00051-2
109. Bluthe R.M., N. Castanon, F. Pousset, A. Bristow, C. Ball, J. Lestage, B. Michaud, K.W. Kelley, R. Dantzer: Central injection of IL-10 antagonizes the behavioural effects of lipopolysaccharide in rats. Psychoneuroendocrinology 24, 301-311 (1999)
doi:10.1016/S0306-4530(98)00077-8
110. Kelley K.W., R.M. Bluthe, R. Dantzer, J.H. Zhou, W.H. Shen, R.W. Johnson, S.R. Broussard: Cytokine-induced sickness behavior. Brain Behav Immun 17 Suppl 1, S112-118 (2003)
doi:10.1016/S0889-1591(02)00077-6
111. Wieczorek M., A.H. Swiergiel, H. Pournajafi-Nazarloo, A.J. Dunn: Physiological and behavioral responses to interleukin-1beta and LPS in vagotomized mice. Physiol Behav 85, 500-511 (2005)
doi:10.1016/j.physbeh.2005.05.012
112. Lacroix S., S. Rivest: Functional circuitry in the brain of immune-challenged rats: partial involvement of prostaglandins. J Comp Neurol 387, 307-324 (1997)
doi:10.1002/(SICI)1096-9861(19971020)387:2<307::AID-CNE11>3.0.CO;2-R
113. Sagar S.M., K.J. Price, N.W. Kasting, F.R. Sharp: Anatomic patterns of Fos immunostaining in rat brain following systemic endotoxin administration. Brain Res Bull 36, 381-392 (1995)
doi:10.1016/0361-9230(94)00217-O
114. Aid S., R. Langenbach, F. Bosetti: Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2. J Neuroinflammation 5, 17 (2008)
doi:10.1186/1742-2094-5-17
115. Morita I.: Distinct functions of COX-1 and COX-2. Prostaglandins Other Lipid Mediat 68-69, 165-175 (2002)
doi:10.1016/S0090-6980(02)00029-1
116. Dunn A.J., A.H. Swiergiel, H. Zhang, N. Quan: Reduced ingestion of sweetened milk induced by interleukin-1 and lipopolysaccharide is associated with induction of cyclooxygenase-2 in brain endothelia. Neuroimmunomodulation 13, 96-104 (2006) doi:10.1159/000096291
117. Teeling J.L., L.M. Felton, R.M. Deacon, C. Cunningham, J.N. Rawlins, V.H. Perry: Sub-pyrogenic systemic inflammation impacts on brain and behavior, independent of cytokines. Brain Behav Immun 21, 836-850 (2007)
doi:10.1016/j.bbi.2007.01.012
118. Dunn A.J.: Effects of the IL-1 receptor antagonist on the IL-1- and endotoxin-induced activation of the HPA axis and cerebral biogenic amines in mice. Neuroimmunomodulation 7, 36-45 (2000)
doi:10.1159/000026418
119. Swiergiel A.H., A.J. Dunn: Distinct roles for cyclooxygenases 1 and 2 in interleukin-1-induced behavioral changes. J Pharmacol Exp Ther 302, 1031-1036 (2002)
doi:10.1124/jpet.102.036640
120. Maes M., S. Scharpe, E. Bosmans, M. Vandewoude, E. Suy, W. Uyttenbroeck, W. Cooreman, C. Vandervorst, J. Raus: Disturbances in acute phase plasma proteins during melancholia: additional evidence for the presence of an inflammatory process during that illness. Prog Neuropsychopharmacol Biol Psychiatry 16, 501-515 (1992)
doi:10.1016/0278-5846(92)90056-K
121. Reichenberg A., R. Yirmiya, A. Schuld, T. Kraus, M. Haack, A. Morag, T. Pollmacher: Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 58, 445-452 (2001)
doi:10.1001/archpsyc.58.5.445
122. Alesci S., P.E. Martinez, S. Kelkar, I. Ilias, D.S. Ronsaville, S.J. Listwak, A.R. Ayala, J. Licinio, H.K. Gold, M.A. Kling, G.P. Chrousos, P.W. Gold: Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications. J Clin Endocrinol Metab 90, 2522-2530 (2005)
doi:10.1210/jc.2004-1667
123. Bremmer M.A., A.T. Beekman, D.J. Deeg, B.W. Penninx, M.G. Dik, C.E. Hack, W.J. Hoogendijk: Inflammatory markers in late-life depression: results from a population-based study. J Affect Disord 106, 249-255 (2008)
doi:10.1016/j.jad.2007.07.002
124. Himmerich H., S. Fulda, J. Linseisen, H. Seiler, G. Wolfram, S. Himmerich, K. Gedrich, S. Kloiber, S. Lucae, M. Ising, M. Uhr, F. Holsboer, T. Pollmacher: Depression, comorbidities and the TNF-alpha system. Eur Psychiatry 23, 421-429 (2008)
doi:10.1016/j.eurpsy.2008.03.013
125. Humphreys D., L. Schlesinger, M. Lopez, A.V. Araya: Interleukin-6 production and deregulation of the hypothalamic-pituitary-adrenal axis in patients with major depressive disorders. Endocrine 30, 371-376 (2006)
doi:10.1007/s12020-006-0016-1
126. Kim Y.K., K.S. Na, K.H. Shin, H.Y. Jung, S.H. Choi, J.B. Kim: Cytokine imbalance in the pathophysiology of major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 31, 1044-1053 (2007)
doi:10.1016/j.pnpbp.2007.03.004
127. Lanquillon S., J.C. Krieg, U. Bening-Abu-Shach, H. Vedder: Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22, 370-379 (2000) doi:10.1016/S0893-133X(99)00134-7
128. Mikova O., R. Yakimova, E. Bosmans, G. Kenis, M. Maes: Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis. Eur Neuropsychopharmacol 11, 203-208 (2001)
doi:10.1016/S0924-977X(01)00081-5
129. Sutcigil L., C. Oktenli, U. Musabak, A. Bozkurt, A. Cansever, O. Uzun, S.Y. Sanisoglu, Z. Yesilova, N. Ozmenler, A. Ozsahin, A. Sengul: Pro- and anti-inflammatory cytokine balance in major depression: effect of sertraline therapy. Clin Dev Immunol 2007, 76396 (2007)
doi:10.1155/2007/76396
130. Yang K., G. Xie, Z. Zhang, C. Wang, W. Li, W. Zhou, Y. Tang: Levels of serum interleukin (IL)-6, IL-1beta, tumour necrosis factor-alpha and leptin and their correlation in depression. Aust N Z J Psychiatry 41, 266-273 (2007)
doi:10.1080/00048670601057759
131. Leo R., G. Di Lorenzo, M. Tesauro, C. Razzini, G.B. Forleo, G. Chiricolo, C. Cola, M. Zanasi, A. Troisi, A. Siracusano, R. Lauro, F. Romeo: Association between enhanced soluble CD40 ligand and proinflammatory and prothrombotic states in major depressive disorder: pilot observations on the effects of selective serotonin reuptake inhibitor therapy. J Clin Psychiatry 67, 1760-1766 (2006)
132. Owen B.M., D. Eccleston, I.N. Ferrier, A.H. Young: Raised levels of plasma interleukin-1beta in major and postviral depression. Acta Psychiatr Scand 103, 226-228 (2001)
doi:10.1034/j.1600-0447.2001.00162.x
133. Maes M.: The immunoregulatory effects of antidepressants. Hum Psychopharmacol 16, 95-103 (2001)
doi:10.1002/hup.191
134. Muller N., M.J. Schwarz, S. Dehning, A. Douhe, A. Cerovecki, B. Goldstein-Muller, I. Spellmann, G. Hetzel, K. Maino, N. Kleindienst, H.J. Moller, V. Arolt, M. Riedel: The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 11, 680-684 (2006)
doi:10.1038/sj.mp.4001805
135. de Jong J.C., P.B. van den Berg, H. Tobi, L.T. de Jong-van den Berg: Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects. Br J Clin Pharmacol 55, 591-595 (2003)
doi:10.1046/j.0306-5251.2002.01770.x
136. Steiner J., H. Bielau, R. Brisch, P. Danos, O. Ullrich, C. Mawrin, H.G. Bernstein, B. Bogerts: Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res 42, 151-157 (2008)
doi:10.1016/j.jpsychires.2006.10.013
137. Kim Y.K., S.W. Lee, S.H. Kim, S.H. Shim, S.W. Han, S.H. Choi, B.H. Lee: Differences in cytokines between non-suicidal patients and suicidal patients in major depression. Prog Neuropsychopharmacol Biol Psychiatry 32, 356-361 (2008)
doi:10.1016/j.pnpbp.2007.08.041
138. Dierynck I., A. Bernard, H. Roels, M. De Ley: Potent inhibition of both human interferon-gamma production and biologic activity by the Clara cell protein CC16. Am J Respir Cell Mol Biol 12, 205-210 (1995)
139. Eller T., V. Vasar, J. Shlik, E. Maron: Pro-inflammatory cytokines and treatment response to escitalopram in major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 32, 445-450 (2008)
doi:10.1016/j.pnpbp.2007.09.015
140. O'Brien S.M., P. Scully, P. Fitzgerald, L.V. Scott, T.G. Dinan: Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J Psychiatr Res 41, 326-331 (2007)
doi:10.1016/j.jpsychires.2006.05.013
141. Huang T.L., C.T. Lee: T-helper 1/T-helper 2 cytokine imbalance and clinical phenotypes of acute-phase major depression. Psychiatry Clin Neurosci 61, 415-420 (2007)
doi:10.1111/j.1440-1819.2007.01686.x
142. Rothermundt M., V. Arolt, J. Fenker, H. Gutbrodt, M. Peters, H. Kirchner: Different immune patterns in melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin Neurosci 251, 90-97 (2001)
doi:10.1007/s004060170058
143. Kaestner F., M. Hettich, M. Peters, W. Sibrowski, G. Hetzel, G. Ponath, V. Arolt, U. Cassens, M. Rothermundt: Different activation patterns of proinflammatory cytokines in melancholic and non-melancholic major depression are associated with HPA axis activity. J Affect Disord 87, 305-311 (2005)
doi:10.1016/j.jad.2005.03.012
144. Anisman H., A.V. Ravindran, J. Griffiths, Z. Merali: Interleukin-1 beta production in dysthymia before and after pharmacotherapy. Biol Psychiatry 46, 1649-1655 (1999)
doi:10.1016/S0006-3223(99)00211-5
145. Vaccarino V., B.D. Johnson, D.S. Sheps, S.E. Reis, S.F. Kelsey, V. Bittner, T. Rutledge, L.J. Shaw, G. Sopko, C.N. Bairey Merz: Depression, inflammation, and incident cardiovascular disease in women with suspected coronary ischemia: the National Heart, Lung, and Blood Institute-sponsored WISE study. J Am Coll Cardiol 50, 2044-2050 (2007)
doi:10.1016/j.jacc.2007.07.069
146. Elovainio M., L. Keltikangas-Jarvinen, L. Pulkki-Raback, M. Kivimaki, S. Puttonen, L. Viikari, L. Rasanen, K. Mansikkaniemi, J. Viikari, O.T. Raitakari: Depressive symptoms and C-reactive protein: the Cardiovascular Risk in Young Finns Study. Psychol Med 36, 797-805 (2006)
doi:10.1017/S0033291706007574
147. Danner M., S.V. Kasl, J.L. Abramson, V. Vaccarino: Association between depression and elevated C-reactive protein. Psychosom Med 65, 347-356 (2003)
doi:10.1097/01.PSY.0000041542.29808.01
148. Liukkonen T., S. Silvennoinen-Kassinen, J. Jokelainen, P. Rasanen, M. Leinonen, V.B. Meyer-Rochow, M. Timonen: The association between C-reactive protein levels and depression: Results from the northern Finland 1966 birth cohort study. Biol Psychiatry 60, 825-830 (2006)
doi:10.1016/j.biopsych.2006.02.016
149. Frasure-Smith N., F. Lesperance, M.R. Irwin, C. Sauve, J. Lesperance, P. Theroux: Depression, C-reactive protein and two-year major adverse cardiac events in men after acute coronary syndromes. Biol Psychiatry 62, 302-308 (2007)
doi:10.1016/j.biopsych.2006.09.029
150. Abraham J., C.Y. Campbell, A. Cheema, T.J. Gluckman, R.S. Blumenthal, P. Danyi: C-reactive protein in cardiovascular risk assessment: a review of the evidence. J Cardiometab Syndr 2, 119-123 (2007)
doi:10.1111/j.1559-4564.2007.05950.x
151. Katrinchak C., K. Fritz: Clinical implications of C-reactive protein as a predictor of vascular risk. J Am Acad Nurse Pract 19, 335-340 (2007)
doi:10.1111/j.1745-7599.2007.00234.x
152. Lowe G.D., P.M. Sweetnam, J.W. Yarnell, A. Rumley, C. Rumley, D. Bainton, Y. Ben-Shlomo: C-reactive protein, fibrin D-dimer, and risk of ischemic heart disease: the Caerphilly and Speedwell studies. Arterioscler Thromb Vasc Biol 24, 1957-1962 (2004)
doi:10.1161/01.ATV.0000141842.27810.a9
153. Arbelaez J.J., A.A. Ariyo, R.M. Crum, L.P. Fried, D.E. Ford: Depressive symptoms, inflammation, and ischemic stroke in older adults: a prospective analysis in the cardiovascular health study. J Am Geriatr Soc 55, 1825-1830 (2007)
doi:10.1111/j.1532-5415.2007.01393.x
154. Whooley M.A., C.M. Caska, B.E. Hendrickson, M.A. Rourke, J. Ho, S. Ali: Depression and inflammation in patients with coronary heart disease: findings from the Heart and Soul Study. Biol Psychiatry 62, 314-320 (2007)
doi:10.1016/j.biopsych.2006.10.016
155. Guzman A., L.H. Tonelli, D. Roberts, J.W. Stiller, M.A. Jackson, J.J. Soriano, S. Yousufi, K.J. Rohan, H. Komarow, T.T. Postolache: Mood-worsening with high-pollen-counts and seasonality: a preliminary report. J Affect Disord 101, 269-274 (2007)
doi:10.1016/j.jad.2006.11.026
156. Postolache T.T., J.W. Stiller, R. Herrell, M.A. Goldstein, S.S. Shreeram, R. Zebrak, C.M. Thrower, J. Volkov, M.J. No, I. Volkov, K.J. Rohan, J. Redditt, M. Parmar, F. Mohyuddin, C. Olsen, M. Moca, L.H. Tonelli, K. Merikangas, H.D. Komarow: Tree pollen peaks are associated with increased nonviolent suicide in women. Mol Psychiatry 10, 232-235 (2005)
doi:10.1038/sj.mp.4001620
157. Postolache T.T., M. Lapidus, E.R. Sander, P. Langenberg, R.G. Hamilton, J.J. Soriano, J.S. McDonald, N. Furst, J. Bai, D.A. Scrandis, J.A. Cabassa, J.W. Stiller, T. Balis, A. Guzman, A. Togias, L.H. Tonelli: Changes in allergy symptoms and depression scores are positively correlated in patients with recurrent mood disorders exposed to seasonal peaks in aeroallergens. ScientificWorldJournal 7, 1968-1977 (2007)
158. Postolache T.T., H.D. Komarow: Allergy, depression, and suicide. Directions in Psychiatry 25, 59-66 (2005)
159. Tonelli L.H., J. Stiller, D. Rujescu, I. Giegling, B. Schneider, K. Maurer, A. Schnabel, H.J. Moller, H.H. Chen, T.T. Postolache: Elevated cytokine expression in the orbitofrontal cortex of victims of suicide. Acta Psychiatr Scand 117, 198-206 (2008)
doi:10.1111/j.1600-0447.2007.01128.x
160. Loftis J.M., M. Huckans, S. Ruimy, D.J. Hinrichs, P. Hauser: Depressive symptoms in patients with chronic hepatitis C are correlated with elevated plasma levels of interleukin-1beta and tumor necrosis factor-alpha. Neurosci Lett 430, 264-268 (2008)
doi:10.1016/j.neulet.2007.11.001
161. Dunn R.T., T.A. Kimbrell, T.A. Ketter, M.A. Frye, M.W. Willis, D.A. Luckenbaugh, R.M. Post: Principal components of the Beck Depression Inventory and regional cerebral metabolism in unipolar and bipolar depression. Biol Psychiatry 51, 387-399 (2002)
doi:10.1016/S0006-3223(01)01244-6
162. Carrieri P.B., V. Provitera, T. De Rosa, G. Tartaglia, F. Gorga, O. Perrella: Profile of cerebrospinal fluid and serum cytokines in patients with relapsing-remitting multiple sclerosis: a correlation with clinical activity. Immunopharmacol Immunotoxicol 20, 373-382 (1998)
doi:10.3109/08923979809034820
163. Hautecoeur P., G. Forzy, P. Gallois, V. Demirbilek, O. Feugas: Variations of IL2, IL6, TNF alpha plasmatic levels in relapsing remitting multiple sclerosis. Acta Neurol Belg 97, 240-243 (1997)
164. Kahl K.G., N. Kruse, H. Faller, H. Weiss, P. Rieckmann: Expression of tumor necrosis factor-alpha and interferon-gamma mRNA in blood cells correlates with depression scores during an acute attack in patients with multiple sclerosis. Psychoneuroendocrinology 27, 671-681 (2002)
doi:10.1016/S0306-4530(01)00068-3
165. Monteyne P., C.J. Sindic: Data on cytokine mRNA expression in CSF and peripheral blood mononuclear cells from MS patients as detected by PCR. Mult Scler 4, 143-146 (1998)
166. Monteyne P., V. Van Laere, R. Marichal, C.J. Sindic: Cytokine mRNA expression in CSF and peripheral blood mononuclear cells in multiple sclerosis: detection by RT-PCR without in vitro stimulation. J Neuroimmunol 80, 137-142 (1997)
doi:10.1016/S0165-5728(97)00148-3
167. Pucak M.L., K.A. Carroll, D.A. Kerr, A.I. Kaplin: Neuropsychiatric manifestations of depression in multiple sclerosis: neuroinflammatory, neuroendocrine, and neurotrophic mechanisms in the pathogenesis of immune-mediated depression. Dialogues Clin Neurosci 9, 125-139 (2007)
168. Musselman D.L., A.H. Miller, M.R. Porter, A. Manatunga, F. Gao, S. Penna, B.D. Pearce, J. Landry, S. Glover, J.S. McDaniel, C.B. Nemeroff: Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings. Am J Psychiatry 158, 1252-1257 (2001)
doi:10.1176/appi.ajp.158.8.1252
169. Soygur H., O. Palaoglu, E.S. Akarsu, E.S. Cankurtaran, E. Ozalp, L. Turhan, I.H. Ayhan: Interleukin-6 levels and HPA axis activation in breast cancer patients with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 31, 1242-1247 (2007)
doi:10.1016/j.pnpbp.2007.05.001
170. Jacobson C.M., B. Rosenfeld, H. Pessin, W. Breitbart: Depression and IL-6 blood plasma concentrations in advanced cancer patients. Psychosomatics 49, 64-66 (2008)
doi:10.1176/appi.psy.49.1.64
171. Capuron L., A. Ravaud, P.J. Neveu, A.H. Miller, M. Maes, R. Dantzer: Association between decreased serum tryptophan concentrations and depressive symptoms in cancer patients undergoing cytokine therapy. Mol Psychiatry 7, 468-473 (2002)
doi:10.1038/sj.mp.4000995
172. Friebe A., M.J. Schwarz, M. Schmid-Wendtner, M. Volkenandt, F. Schmidt, M. Horn, G. Janssen, M. Schaefer: Pretreatment levels of sTNF-R1 and sIL-6R are associated with a higher vulnerability for IFN-alpha-induced depressive symptoms in patients with malignant melanoma. J Immunother 30, 333-337 (2007)
doi:10.1097/01.cji.0000211346.19330.c9
173. Wichers M.C., G. Kenis, C. Leue, G. Koek, G. Robaeys, M. Maes: Baseline immune activation as a risk factor for the onset of depression during interferon-alpha treatment. Biol Psychiatry 60, 77-79 (2006)
doi:10.1016/j.biopsych.2005.11.024
174. Capuron L., G. Neurauter, D.L. Musselman, D.H. Lawson, C.B. Nemeroff, D. Fuchs, A.H. Miller: Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biol Psychiatry 54, 906-914 (2003)
doi:10.1016/S0006-3223(03)00173-2
175. Capuron L., C.L. Raison, D.L. Musselman, D.H. Lawson, C.B. Nemeroff, A.H. Miller: Association of exaggerated HPA axis response to the initial injection of interferon-alpha with development of depression during interferon-alpha therapy. Am J Psychiatry 160, 1342-1345 (2003)
doi:10.1176/appi.ajp.160.7.1342
176. Kraus M.R., O. Al-Taie, A. Schafer, M. Pfersdorff, K.P. Lesch, M. Scheurlen: Serotonin-1A receptor gene HTR1A variation predicts interferon-induced depression in chronic hepatitis C. Gastroenterology 132, 1279-1286 (2007)
doi:10.1053/j.gastro.2007.02.053
177. Angelino A.F., G.J. Treisman: Evidence-informed assessment and treatment of depression in HCV and interferon-treated patients. Int Rev Psychiatry 17, 471-476 (2005)
doi:10.1080/02646830500381567
178. Bonaccorso S., V. Marino, M. Biondi, F. Grimaldi, F. Ippoliti, M. Maes: Depression induced by treatment with interferon-alpha in patients affected by hepatitis C virus. J Affect Disord 72, 237-241 (2002)
doi:10.1016/S0165-0327(02)00264-1
179. Hunt C.M., J.A. Dominitz, B.P. Bute, B. Waters, U. Blasi, D.M. Williams: Effect of interferon-alpha treatment of chronic hepatitis C on health-related quality of life. Dig Dis Sci 42, 2482-2486 (1997)
doi:10.1023/A:1018852309885
180. Loftis J.M., P. Hauser: The phenomenology and treatment of interferon-induced depression. J Affect Disord 82, 175-190 (2004)
doi:10.1016/j.jad.2004.04.002
181. Valentine A.D., C.A. Meyers: Neurobehavioral effects of interferon therapy. Curr Psychiatry Rep 7, 391-395 (2005)
doi:10.1007/s11920-005-0042-3
182. Malaguarnera M., A. Laurino, I. Di Fazio, G. Pistone, M. Castorina, N. Guccione, L. Rampello: Neuropsychiatric effects and type of IFN-alpha in chronic hepatitis C. J Interferon Cytokine Res 21, 273-278 (2001)
doi:10.1089/107999001300177457
183. Krueger J.M., F.J. Obal, J. Fang, T. Kubota, P. Taishi: The role of cytokines in physiological sleep regulation. Ann N Y Acad Sci 933, 211-221 (2001)
184. Irwin M.: Effects of sleep and sleep loss on immunity and cytokines. Brain Behav Immun 16, 503-512 (2002)
doi:10.1016/S0889-1591(02)00003-X
185. Capuron L., P. Hauser, D. Hinze-Selch, A.H. Miller, P.J. Neveu: Treatment of cytokine-induced depression. Brain Behav Immun 16, 575-580 (2002)
doi:10.1016/S0889-1591(02)00007-7
186. Collier J., R. Chapman: Combination therapy with interferon-alpha and ribavirin for hepatitis C: practical treatment issues. BioDrugs 15, 225-238 (2001)
doi:10.2165/00063030-200115040-00003
187. Kraus M.R., A. Schafer, K. Schottker, C. Keicher, B. Weissbrich, I. Hofbauer, M. Scheurlen: Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study. Gut 57, 531-536 (2008)
doi:10.1136/gut.2007.131607
188. Bonaccorso S., A. Puzella, V. Marino, M. Pasquini, M. Biondi, M. Artini, C. Almerighi, M. Levrero, B. Egyed, E. Bosmans, H.Y. Meltzer, M. Maes: Immunotherapy with interferon-alpha in patients affected by chronic hepatitis C induces an intercorrelated stimulation of the cytokine network and an increase in depressive and anxiety symptoms. Psychiatry Res 105, 45-55 (2001)
doi:10.1016/S0165-1781(01)00315-8
189. Corssmit E.P., R. Heijligenberg, C.E. Hack, E. Endert, H.P. Sauerwein, J.A. Romijn: Effects of interferon-alpha (IFN-alpha) administration on leucocytes in healthy humans. Clin Exp Immunol 107, 359-363 (1997)
doi:10.1111/j.1365-2249.1997.269-ce1161.x
190. Wichers M.C., G. Kenis, G.H. Koek, G. Robaeys, N.A. Nicolson, M. Maes: Interferon-alpha-induced depressive symptoms are related to changes in the cytokine network but not to cortisol. J Psychosom Res 62, 207-214 (2007)
doi:10.1016/j.jpsychores.2006.09.007
191. Schiepers O.J., M.C. Wichers, M. Maes: Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 29, 201-217 (2005)
doi:10.1016/j.pnpbp.2004.11.003
192. Wichers M., M. Maes: The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol 5, 375-388 (2002)
doi:10.1017/S1461145702003103
193. Mohr D.C., D.E. Goodkin, W. Likosky, N. Gatto, K.A. Baumann, R.A. Rudick: Treatment of depression improves adherence to interferon beta-1b therapy for multiple sclerosis. Arch Neurol 54, 531-533 (1997)
194. Borras C., J. Rio, J. Porcel, M. Barrios, M. Tintore, X. Montalban: Emotional state of patients with relapsing-remitting MS treated with interferon beta-1b. Neurology 52, 1636-1639 (1999)
195. Patten S.B., L.M. Metz: Interferon beta-1 a and depression in relapsing-remitting multiple sclerosis: an analysis of depression data from the PRISMS clinical trial. Mult Scler 7, 243-248 (2001)
196. Patten S.B., L.M. Metz: Interferon beta1a and depression in secondary progressive MS: data from the SPECTRIMS Trial. Neurology 59, 744-746 (2002)
197. Goeb J.L., C. Even, G. Nicolas, B. Gohier, F. Dubas, J.B. Garre: Psychiatric side effects of interferon-beta in multiple sclerosis. Eur Psychiatry 21, 186-193 (2006)
doi:10.1016/j.eurpsy.2005.09.013
198. Kraus M.R., A. Schafer, H. Faller, H. Csef, M. Scheurlen: Psychiatric symptoms in patients with chronic hepatitis C receiving interferon alfa-2b therapy. J Clin Psychiatry 64, 708-714 (2003)
199. Dieperink E., M. Willenbring, S.B. Ho: Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: A review. Am J Psychiatry 157, 867-876 (2000)
doi:10.1176/appi.ajp.157.6.867
200. Lieb K., M.A. Engelbrecht, O. Gut, B.L. Fiebich, J. Bauer, G. Janssen, M. Schaefer: Cognitive impairment in patients with chronic hepatitis treated with interferon alpha (IFNalpha): results from a prospective study. Eur Psychiatry 21, 204-210 (2006)
doi:10.1016/j.eurpsy.2004.09.030
201. George J., S. Bleasdale, S.J. Singleton: Causes and prognosis of delirium in elderly patients admitted to a district general hospital. Age Ageing 26, 423-427 (1997)
doi:10.1093/ageing/26.6.423
202. Rudolph J.L., B. Ramlawi, G.A. Kuchel, J.E. McElhaney, D. Xie, F.W. Sellke, K. Khabbaz, S.E. Levkoff, E.R. Marcantonio: Chemokines are associated with delirium after cardiac surgery. J Gerontol A Biol Sci Med Sci 63, 184-189 (2008)
203. Adamis D., A. Treloar, F.C. Martin, N. Gregson, G. Hamilton, A.J. Macdonald: APOE and cytokines as biological markers for recovery of prevalent delirium in elderly medical inpatients. Int J Geriatr Psychiatry 22, 688-694 (2007)
doi:10.1002/gps.1732
204. Wilson K., C. Broadhurst, M. Diver, M. Jackson, P. Mottram: Plasma insulin growth factor-1 and incident delirium in older people. Int J Geriatr Psychiatry 20, 154-159 (2005)
doi:10.1002/gps.1265
205. Broadhurst C., K. Wilson: Immunology of delirium: new opportunities for treatment and research. Br J Psychiatry 179, 288-289 (2001)
doi:10.1192/bjp.179.4.288
206. Kudoh A., H. Takase, H. Katagai, T. Takazawa: Postoperative interleukin-6 and cortisol concentrations in elderly patients with postoperative confusion. Neuroimmunomodulation 12, 60-66 (2005)
doi:10.1159/000082365
207. Pfister D., M. Siegemund, S. Dell-Kuster, P. Smielewski, S. Ruegg, S.P. Strebel, S.C. Marsch, H. Pargger, L.A. Steiner: Cerebral perfusion in sepsis-associated delirium. Crit Care 12, R63 (2008)
doi:10.1186/cc6891
208. Beloosesky Y., J. Grinblat, A. Pirotsky, A. Weiss, D. Hendel: Different C-reactive protein kinetics in post-operative hip-fractured geriatric patients with and without complications. Gerontology 50, 216-222 (2004)
doi:10.1159/000078350
209. Beloosesky Y., D. Hendel, A. Weiss, A. Hershkovitz, J. Grinblat, A. Pirotsky, V. Barak: Cytokines and C-reactive protein production in hip-fracture-operated elderly patients. J Gerontol A Biol Sci Med Sci 62, 420-426 (2007)
210. Rafnsson S.B., I.J. Deary, F.B. Smith, M.C. Whiteman, F.G. Fowkes: Cardiovascular diseases and decline in cognitive function in an elderly community population: the Edinburgh Artery Study. Psychosom Med 69, 425-434 (2007)
doi:10.1097/psy.0b013e318068fce4
211. Schram M.T., S.M. Euser, A.J. de Craen, J.C. Witteman, M. Frolich, A. Hofman, J. Jolles, M.M. Breteler, R.G. Westendorp: Systemic markers of inflammation and cognitive decline in old age. J Am Geriatr Soc 55, 708-716 (2007)
doi:10.1111/j.1532-5415.2007.01159.x
212. Bermejo P., S. Martin-Aragon, J. Benedi, C. Susin, E. Felici, P. Gil, J.M. Ribera, A.M. Villar: Differences of peripheral inflammatory markers between mild cognitive impairment and Alzheimer's disease. Immunol Lett 117, 198-202 (2008)
doi:10.1016/j.imlet.2008.02.002
213. Mustafa A., L. Lannfelt, L. Lilius, A. Islam, B. Winblad, A. Adem: Decreased plasma insulin-like growth factor-I level in familial Alzheimer's disease patients carrying the Swedish APP 670/671 mutation. Dement Geriatr Cogn Disord 10, 446-451 (1999)
doi:10.1159/000017188
214. Cazzullo C.L., E. Sacchetti, A. Galluzzo, A. Panariello, F. Colombo, A. Zagliani, M. Clerici: Cytokine profiles in drug-naive schizophrenic patients. Schizophr Res 47, 293-298 (2001)
doi:10.1016/S0920-9964(00)00046-3
215. Maes M., E. Bosmans, R. Ranjan, E. Vandoolaeghe, H.Y. Meltzer, M. De Ley, R. Berghmans, G. Stans, R. Desnyder: Lower plasma CC16, a natural anti-inflammatory protein, and increased plasma interleukin-1 receptor antagonist in schizophrenia: effects of antipsychotic drugs. Schizophr Res 21, 39-50 (1996)
doi:10.1016/0920-9964(96)00029-1
216. Naudin J., C. Capo, B. Giusano, J.L. Mege, J.M. Azorin: A differential role for interleukin-6 and tumor necrosis factor-alpha in schizophrenia? Schizophr Res 26, 227-233 (1997)
doi:10.1016/S0920-9964(97)00059-5
217. Naudin J., J.L. Mege, J.M. Azorin, D. Dassa: Elevated circulating levels of IL-6 in schizophrenia. Schizophr Res 20, 269-273 (1996)
doi:10.1016/0920-9964(96)00014-X
218. Zhang X.Y., D.F. Zhou, P.Y. Zhang, G.Y. Wu, L.Y. Cao, Y.C. Shen: Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology. Schizophr Res 57, 247-258 (2002)
doi:10.1016/S0920-9964(01)00296-1
219. Erbagci A.B., H. Herken, O. Koyluoglu, N. Yilmaz, M. Tarakcioglu: Serum IL-1beta, sIL-2R, IL-6, IL-8 and TNF-alpha in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment. Mediators Inflamm 10, 109-115 (2001)
doi:10.1080/09629350120072761
220. Zhang X.Y., D.F. Zhou, L.Y. Cao, G.Y. Wu, Y.C. Shen: Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics. Neuropsychopharmacology 30, 1532-1538 (2005)
doi:10.1038/sj.npp.1300756
221. Chen X., K.S. Kendler: Interleukin 3 and schizophrenia. Am J Psychiatry 165, 13-14 (2008)
doi:10.1176/appi.ajp.2007.07121868
222. Lencz T., T.V. Morgan, M. Athanasiou, B. Dain, C.R. Reed, J.M. Kane, R. Kucherlapati, A.K. Malhotra: Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia. Mol Psychiatry 12, 572-580 (2007)
doi:10.1038/sj.mp.4001983
223. Neri S., D. Pulvirenti, G. Bertino: Psychiatric symptoms induced by antiviral therapy in chronic hepatitis C: comparison between interferon-alpha-2a and interferon-alpha-2b. Clin Drug Investig 26, 655-662 (2006)
doi:10.2165/00044011-200626110-00005
224. Quarantini L.C., S.C. Cruz, S.C. Batista-Neves, R. Parana, A. Miranda-Scippa, R.A. Bressan: Psychosis during peginterferon-alpha 2a and ribavirin therapy: case report. Braz J Infect Dis 10, 406-407 (2006)
doi:10.1590/S1413-86702006000600010
225. Cazzullo C.L., E. Sacchetti, A. Galluzzo, A. Panariello, A. Adorni, M. Pegoraro, S. Bosis, F. Colombo, D. Trabattoni, A. Zagliani, M. Clerici: Cytokine profiles in schizophrenic patients treated with risperidone: a 3-month follow-up study. Prog Neuropsychopharmacol Biol Psychiatry 26, 33-39 (2002)
doi:10.1016/S0278-5846(01)00221-4
226. Zhang X.Y., D.F. Zhou, L.Y. Cao, P.Y. Zhang, G.Y. Wu, Y.C. Shen: Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. J Clin Psychiatry 65, 940-947 (2004)
227. Lin A., G. Kenis, S. Bignotti, G.J. Tura, R. De Jong, E. Bosmans, R. Pioli, C. Altamura, S. Scharpe, M. Maes: The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr Res 32, 9-15 (1998)
doi:10.1016/S0920-9964(98)00034-6
228. Maes M., L. Bocchio Chiavetto, S. Bignotti, G. Battisa Tura, R. Pioli, F. Boin, G. Kenis, E. Bosmans, R. de Jongh, A. Lin, G. Racagni, C.A. Altamura: Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics. Eur Neuropsychopharmacol 10, 119-124 (2000)
doi:10.1016/S0924-977X(99)00062-0
229. Maes M., L. Bocchio Chiavetto, S. Bignotti, G.J. Battisa Tura, R. Pioli, F. Boin, G. Kenis, E. Bosmans, R. de Jongh, C.A. Altamura: Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr Res 54, 281-291 (2002)
doi:10.1016/S0920-9964(00)00094-3
230. Inglot A.D., J. Leszek, E. Piasecki, A. Sypula: Interferon responses in schizophrenia and major depressive disorders. Biol Psychiatry 35, 464-473 (1994)
doi:10.1016/0006-3223(94)90045-0
Key Words: Cytokines, Stress, Depression, Sickness Behavior, Immunotherapy, Neurotransmission, Review
Send correspondence to: Hymie Anisman, Institute of Neuroscience, Carleton University, Ottawa, Ontario K1S 5B6, Canada, Tel: 613-520-2699, Fax: 613-520-4052, E-mail: hanisman@ccs.carleton.ca