[Frontiers in Bioscience 10, 2193-2216, September 1, 2005]


Andrej A. Romanovsky 1, Maria C. Almeida 1, David M. Aronoff 2, Andrei I. Ivanov 3, Jan P. Konsman 4, Alexandre A. Steiner 1, and Victoria F. Turek 5

1Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital and Medical Center, 350 West Thomas Road, Phoenix, AZ 85013, USA, 2Division of Infectious Diseases, Department of Internal Medicine, University of Michigan Health System, 1500 West Medical Center Drive, Ann Arbor, MI 48109, USA, 3Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA, 4Laboratoire de Neurobiologie Integrative, Centre National de la Recherche Scientifique FRE 2723/Institut National de la Recherche Agronomique UR 1244, Institut Francois Magendie, 33077 Bordeaux, France, and 5Department of Behavioral Neuroscience, Oregon Health and Science University, 3181 South West Sam Jackson Park Road, Portland, OR 97239, USA


1. Abstract
2. Introduction
3. New Terminology
4. Experimental Models and Phenomenology
4.1. Studying Fever: Species Used and the Response Latency
4.2. Counting Febrile Phases
4.3. Studying Hypothermia: from "Thermoregulatory Failure" to Specific Mechanisms
5. How the Thermoregulatory Responses to Bacterial Pyrogens Are Initiated
5.1. Signaling of Bacterial Pyrogens
5.2. Early Mediators
6. From the Periphery to the Brain
6.1. Transport
6.2. Entry through the Organum Vasculosum of the Lamina Terminalis
6.3. Vagal Signaling
6.4. The Blood-Brain Barrier as a Signal Transducer
7. Prostaglandin E2 in the Thermoregulatory Responses to Inflammatory Stimuli
7.1. Prostaglandin E2 as a Mediator of Fever
7.2. Do Eicosanoids Mediate Hypothermia?
7.3. Synthesis of Prostaglandin E2 in Systemic Inflammation
7.4. Catabolism
7.5. Mechanism of Action of Prostaglandin E2
8. Neuronal Circuitry of Fever and Hypothermia
9. Peptide "Mediators" and Modulators of Fever and Hypothermia
9.1. Leptin
9.2. Orexins and Neuropeptide Y
9.3. Corticotropin-releasing Factor and Urocortins
9.4. Angiotensin II and Cholecystokinin
9.5. The "Classical" Endogenous Antipyretics
10. Biological Value and Antipyretic Therapy
10.1. Biological Value
10.2. Antipyretic Therapy
11. Instead of Conclusions
12. Acknowledgements
13. References


Systemic inflammation is accompanied by changes in body temperature, either fever or hypothermia. Over the past decade, the rat and mouse have become the predominant animal models, and new species-specific tools (recombinant antibodies and other proteins) and genetic manipulations have been applied to study fever and hypothermia. Remarkable progress has been achieved. It has been established that the same inflammatory agent can induce either fever or hypothermia, depending on several factors. It has also been established that experimental fevers are generally polyphasic, and that different mechanisms underlie different febrile phases. Signaling mechanisms of the most common pyrogen used, bacterial lipopolysaccharide (LPS), have been found to involve the Toll-like receptor 4. The roles of cytokines (such as interleukins-1beta and 6 and tumor necrosis factor-alpha) have been further detailed, and new early mediators (e.g., complement factor 5a and platelet-activating factor) have been proposed. Our understanding of how peripheral inflammatory messengers cross the blood-brain barrier (BBB) has changed. The view that the organum vasculosum of the lamina terminalis is the major port of entry for pyrogenic cytokines has lost its dominant position. The vagal theory has emerged and then fallen. Consensus has been reached that the BBB is not a divider preventing signal transduction, but rather the transducer itself. In the endothelial and perivascular cells of the BBB, upstream signaling molecules (e.g., pro-inflammatory cytokines) are switched to a downstream mediator, prostaglandin (PG) E2. An indispensable role of PGE2 in the febrile response to LPS has been demonstrated in studies with targeted disruption of genes encoding either PGE2-synthesizing enzymes or PGE2 receptors. The PGE2-synthesizing enzymes include numerous phospholipases (PL) A2, cyclooxygenases (COX)-1 and 2, and several newly discovered terminal PGE synthases (PGES). It has been realized that the "physiological," low-scale production of PGE2 and the accelerated synthesis of PGE2 in inflammation are catalyzed by different sets of these enzymes. The "inflammatory" set includes several isoforms of PLA2 and inducible isoforms of COX (COX-2) and microsomal (m) PGES (mPGES-1). The PGE2 receptors are multiple; one of them, EP3 is likely to be a primary "fever receptor." The effector pathways of fever start from EP3-bearing preoptic neurons. These neurons have been found to project to the raphe pallidus, where premotor sympathetic neurons driving thermogenesis in the brown fat and skin vasoconstriction are located. The rapid progress in our understanding of how thermoeffectors are controlled has revealed the inadequacy of set point-based definitions of thermoregulatory responses. New definitions (offered in this review) are based on the idea of balance of active and passive processes and use the term balance point. Inflammatory signaling and thermoeffector pathways involved in fever and hypothermia are modulated by neuropeptides and peptide hormones. Roles for several "new" peptides (e.g., leptin and orexins) have been proposed. Roles for several "old" peptides (e.g., arginine vasopressin, angiotensin II, and cholecystokinin) have been detailed or revised. New pharmacological tools to treat fevers (i.e., selective inhibitors of COX-2) have been rapidly introduced into clinical practice, but have not become magic bullets and appeared to have severe side effects. Several new targets for antipyretic therapy, including mPGES-1, have been identified.