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PubMed
CAVEAT LECTOR
Carol A. Feghali, Ph.D., and Timothy M. Wright, M.D.
Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, E1109 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261
Received 11/06/96; Accepted 12/13/96; On-line 01/01/97
3.1 Cytokines involved in acute inflammation:
Several cytokines play key roles in mediating acute inflammatory reactions, namely IL-1, TNF-alpha, IL-6, IL-11, IL-8 and other chemokines, G-CSF, and GM-CSF (Figure 1). Of these, IL-1 (alpha and ß) and TNF are extremely potent inflammatory molecules: they are the primary cytokines that mediate acute inflammation induced in animals by intradermal injection of bacterial lipopolysaccharide and two of the primary mediators of septic shock.
FIGURE 1: Cytokines involved in acute and chronic inflammatory responses.
The cDNAs for IL-1alpha and ß were cloned in 1984. They are encoded by two different genes, both located on human chromosome 2. Their size ranges from 22-31 kDa for cell-associated molecules, and 17.5 kDa for the secreted molecule (2). Their main cellular sources are mononuclear phagocytes, fibroblasts, keratinocytes, and T and B lymphocytes. Previous synonyms--endogenous pyrogen (EP), mononuclear cell factor, and lymphocyte-activating factor (LAF)--emphasize the role of IL-1 in inflammation. Both IL-1alpha and IL-1ß can trigger fever by enhancing prostaglandin E2 (PGE2) synthesis by the vascular endothelium of the hypothalamus (2) and can stimulate T cell proliferation. In addition, IL-1 elicits the release of histamine from mast cells at the site of inflammation (Figure 2). Histamine then triggers early vasodilation and increase of vascular permeability. The pro-inflammatory effects of IL-1 can be inhibited by IL-1 receptor antagonist (IL-1Ra), originally referred to as IL-1 inhibitor. IL-1Ra is produced by immune complex- or IL-4-stimulated macrophages and by TNF- or GM-CSF-stimulated neutrophils. It bears approximately 20-25% homology at the amino acid level to IL-1alpha and IL-1ß. IL-1Ra inhibits IL-1 action by competing with IL-1 for binding to the IL-1 receptor (IL-1R) (3,4).
FIGURE 2: Inflammatory cytokines, their primary sources and target cells. *IFN-gamma stimulates IgG2a production in the mouse.
Tumor necrosis factors-(TNF)alpha and ß are cytokines that bind to common receptors on the surface of target cells and exhibit several common biological activities. Human TNF-alpha and TNF-ß are of 17 and 25 kDa, respectively. Their corresponding cDNAs were cloned in 1984, and the genes encoding the factors have been mapped to chromosome 6 in humans (5), within the region of the major histocompatibility complex (MHC). TNF-alpha, or cachectin, exists as a trimer (6) and is one of the products of activated macrophages/monocytes, fibroblasts, mast cells, and some T and natural killer (NK) cells (7,8) (Figure 2). TNF-alpha and IL-1 share several pro-inflammatory properties. Like IL-1, TNF-alpha can induce fever, either directly via stimulation of PGE2 synthesis by the vascular endothelium of the hypothalamus, or indirectly by inducing release of IL-1 (2). Both cytokines can stimulate the production of collagenase and PGE2 by synovial cells and thus are believed to contribute to joint damage in inflammatory conditions such as rheumatoid arthritis (2). TNF-alpha also shares an important inflammatory property with IL-6 and IL-11, i.e. the induction of acute phase reactant protein production by the liver. TNF-alpha and IL-1 further exert secondary inflammatory effects by stimulating IL-6 synthesis in several cell types. IL-6 then mediates its own effects and those of TNF-alpha and IL-1 in inducing fever and the acute phase response (2), thereby perpetuating the inflammatory response through a cascade of cytokines with overlapping properties.
TNF-ß, also known as lymphotoxin, is produced by activated T and B lymphocytes. It binds to the same high affinity receptors as TNF-alpha. Its properties are similar to those of TNF-alpha and include the induction of apoptosis (programmed cell death) in many types of transformed, virally infected, and tumor cells, and the stimulation of several PMN effector functions (9).
Although in general the effects of cytokines are exerted locally at the site of their production (autocrine and paracrine), TNF-alpha and TNF-ß, as well as IL-1 and IL-6, have major systemic (endocrine) effects when either produced acutely in large amounts, as in the case of bacterial sepsis, or chronically in lesser amounts, as in the case of chronic infections. During sepsis with Gram negative organisms, lipopolysaccharides (endotoxin) released from bacteria trigger the widespread production of TNF-alpha (and subsequently IL-1 and IL-6) by macrophages. The systemic release of these cytokines has been shown to be responsible for the fever and hypotension that characterize septic shock (8). In an analogous fashion, the production of large amounts of TNF-ß by T lymphocytes in response to "superantigens" such as staphylococcal toxic shock syndrome toxin and enterotoxins are responsible for many of the systemic manifestations (fever, hypotension) of infections with toxin-producing Gram positive organisms (10,11). In addition, the chronic production of TNF is believed to be responsible for the metabolic alterations which result in the cachexia associated with chronic parasitic infections and some cancers (8).
Previous synonyms of IL-6 illustrate some of its biologic activities. They include interferon-ß2 (IFN-ß2), hybridoma/plasmacytoma growth factor, hepatocyte-stimulating factor, B cell stimulatory factor 2 (BSF-2), and B cell differentiation factor (BCDF). IL-6 is a glycoprotein ranging from 21 to 28 kDa depending on the degree of post-translational modification. The IL-6 cDNA was cloned in 1986 and the gene encoding IL-6 was mapped to chromosome 7 in humans (12). IL-6 is produced by a variety of cells including mononuclear phagocytes, T cells, and fibroblasts (12-14). In addition to the stimulation of acute phase protein synthesis by the liver, IL-6 acts as a growth factor for mature B cells and induces their final maturation into antibody-producing plasma cells. It is involved in T cell activation and differentiation, and participates in the induction of IL-2 and IL-2 receptor expression (Figure 2). Some of the regulatory effects of IL-6 involve inhibition of TNF production, providing negative feedback for limiting the acute inflammatory response. Upregulation of IL-6 production has been observed in a variety of chronic inflammatory and autoimmune disorders such as thyroiditis, type I diabetes, rheumatoid arthritis (15,16), systemic sclerosis (17), mesangial proliferative glomerulonephritis and psoriasis, and neoplasms such as cardiac myxoma, renal cell carcinoma, multiple myeloma, lymphoma, and leukemia (15).
IL-11 is a cytokine of 24 kDa encoded by a gene located on the long arm of chromosome 19. The corresponding cDNA was cloned in 1990 (18). IL-11 is produced by bone marrow stromal cells and by some fibroblasts. It is a functional homolog of IL-6 and can replace IL-6 for the proliferation of certain plasmacytoma cell lines (18) and in the induction of acute phase protein secretion in the liver (19). Additional IL-11 activities include stimulation of T cell-dependent B cell immunoglobulin secretion, increased platelet production, and induction of IL-6 expression by CD4+ T cells.
3.1.5 Interleukin-8/chemokines:
IL-8 and other low molecular weight chemokines (e.g. platelet factor 4, IP-10, mig, ENA-78, macrophage inflammatory protein (MIP)-1alpha and ß, MIP-2, monocyte chemoattractant protein-1 (MCP-1/JE), RANTES) belong to a chemotactic cytokine family and are responsible for the chemotactic migration and activation of neutrophils and other cell types (such as monocytes, lymphocytes, basophils, and eosinophils) at sites of inflammation (20,21). The two subsets of the chemokine family, "CXC" (or alpha), "C-C" (or ß) are divided based on presence or absence of an amino acid between the first two of four conserved cysteines. A recent third subset, "C", has only two cysteines and to date only one member, IL-16, has been identified (22). Chemokines have been implicated in inflammatory conditions from acute neutrophil-mediated conditions such as acute respiratory distress syndrome to allergic asthma, arthritis, psoriasis, and chronic inflammatory disorders. To date, at least 27 chemokines have been described. The product of many cell types, including mononuclear phagocytes, antigen-activated T cells, endothelial and epithelial cells, and even neutrophils, IL-8 was previously known as neutrophil chemotactic factor (NCF) and neutrophil activating protein (NAP-1) (20,23). It is the most thoroughly studied chemokine and therefore serves as a prototype for discussing the biologic properties of this rapidly growing family of inflammatory mediators. It consists of a 6-8 kDa protein whose cDNA was cloned by three different laboratories between 1987 and 1989. The corresponding gene has been mapped to chromosome 4 in humans (24). Its main inflammatory impact lies in its chemotactic effects on neutrophils and its ability to stimulate granulocyte activity. In addition, IL-8, IL-1, and TNF are involved in neutrophil recruitment by upregulating cell-surface adhesion molecule expression (such as endothelial leukocyte adhesion molecule, ELAM-1, and intracellular adhesion molecule, ICAM-1), thereby enhancing neutrophil adherence to endothelial cells (2) and facilitating their diapedesis through vessel walls. Thus, IL-8 mediates the recruitment and activation of neutrophils in inflamed tissue (25). IL-8 can be detected in synovial fluid from patients with various inflammatory rheumatic diseases (26), and mucosal levels of IL-8 are elevated in patients with active ulcerative colitis (27).
Other members of this cytokine family, such as NAP-2, GROalpha, GROß, GROgamma, ENA-78, RANTES, MCP-1, MCP-2, MCP-3, platelet factor 4, MIP-1alpha/ß, and MIP-2, are also likely to play important roles in acute inflammation via their shared effects on cell migration. MCP-1 is a chemokine identified in supernatants of blood mononuclear cells. Its production in monocytes is enhanced by inflammatory cytokines. MIP-1alpha and MIP-1ß induce monocyte and T lymphocyte migration. MIP-1alpha, MCP-1, and MIP-2 have been implicated in the pathogenesis of rheumatoid arthritis where they are believed to recruit mononuclear cells into the inflamed regions of the synovium (28). Several other members of the IL-8/chemokine family have been identified but their biologic effects are as yet poorly defined. Two recently identified chemokines, eotaxin and IL-16, have some unique properties and are described below.
Eotaxin was initially described in rodent models of asthma. The human homolog has since been cloned and consists of a 74-amino acid protein. Eotaxin has two of four adjacent cysteines which are highly conserved among ß (C-C) chemokines. At the amino acid level, it is most homologous to the MCP proteins. Eotaxin is a specific chemoattractant for eosinophils. It is produced by cytokine-stimulated epithelial and endothelial cells as well as IL-3-stimulated eosinophils. Eotaxin is implicated in inflammatory bowel disease where its mRNA levels are markedly elevated, especially in ulcerative colitis (29)
IL-16 was originally identified as a chemotactic factor known as lymphocyte chemoattractant factor or lymphotactin. It is the only member of the "C" family of chemokines. The gene encoding IL-16 has been mapped to human chromosome 1 (22). IL-16 is an unusual cytokine in that preformed IL-16 is stored in CD8+ lymphocytes and is secreted upon stimulation with histamine or serotonin (30). It induces chemotaxis of CD4+ T lymphocytes (31,32) (Figure 2) and is believed to initiate T-cell mediated inflammation in asthma (33).
The human IL-17 cDNA was cloned in 1995 based on homology with murine CTLA8 (34). A 1.9 Kb cDNA was found to encode a protein of 17.5 kDa homologous to a product of Herpesvirus saimiri (HVS13) (34). IL-17 is a product of activated T lymphocytes and its biologic activities include stimulation of IL-6 and IL-8 production and enhanced ICAM-1 expression on human foreskin fibroblasts (34).
3.1.9 Colony stimulating factors:
Colony stimulating factors (CSF) are named according to the target cell type whose colony formation in soft agar cultures of bone marrow they induce (35). Of the CSF's, granulocyte-CSF (G-CSF) and granulocyte macrophage-CSF (GM-CSF) participate in acute inflammation. G-CSF was cloned in 1986 and its gene was mapped to chromosome 17 (36). It is a non-glycosylated protein of 19 kDa molecular weight. GM-CSF is a 22 kDa protein. Its full length cDNA sequence was obtained in 1985 and its gene was mapped to chromosome 5 in humans (36). Monocytes, T cells, fibroblasts and endothelial cells activated by macrophage products such as IL-1 or TNF, can produce G-CSF and GM-CSF. Both CSF's can stimulate neutrophils, while GM-CSF can also activate effector functions of eosinophils and mononuclear phagocytes (Figure 2). An example of the pathophysiologic role of GM-CSF is the airway inflammation accompanying asthma, where the implicated cytokines include IL-3, IL-5, and GM-CSF which perpetuate eosinophil activation and survival. In this scenario, the source of GM-CSF may be the alveolar macrophages which are reported to produce two to threefold higher levels of GM-CSF than control macrophages (37). Another possible source for all three cytokines are T cells present in the airways. Additional cytokines such IL-4, IL-13 (both stimulatory) and IFN-gamma (inhibitory) may be involved in the control of IgE synthesis, while IL-1 and TNF-alpha may contribute to the airway inflammation by upregulation of endothelial adhesion molecule expression (37).