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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
4.1 Cytokines involved in chronic inflammation:
Chronic inflammation may develop following acute inflammation and may last for weeks or months, and in some instances for years. During this phase of inflammation, cytokine interactions result in monocyte chemotaxis to the site of inflammation where macrophage activating factors (MAF), such as IFN-gamma, MCP-1, and other molecules then activate the macrophages while migration inhibition factors (MIF), such as GM-CSF (38) and IFN-gamma, retain them at the inflammatory site. The macrophages contribute to the inflammatory process by chronically elaborating low levels of IL-1 and TNF which are responsible for some of the resulting clinical symptoms such as anorexia, cachexia, fever, sleepiness, and leukocytosis.
The cytokines known to mediate chronic inflammatory processes can be divided into those participating in humoral inflammation, such as IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, and transforming growth factor-ß (TGF-ß), and those contributing to cellular inflammation such as IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, interferons (IFNs), IFN-gamma inducing factor (IGIF), TGF-ß, and TNF-alpha and -ß(Figure 1).
4.1.1 Cytokines primarily involved in the humoral inflammatory response:
IL-3, also called multi-CSF, is produced by activated T cells and mast cells. The molecular weight of IL-3 ranges from 14 to 36 kDa. The cloning of the corresponding cDNA was reported in 1984, and the IL-3 gene has been localized to chromosome 5 (39). It stimulates eosinophils and B cell differentiation while it inhibits lymphokine-activated killer (LAK) cell activity (40) (Figure 2). IL-3 shares several biological activities with GM-CSF (41).
IL-4 is expressed as a 15-19 kDa protein and exists as a dimer. The IL-4 gene has been mapped to human chromosome 5, and the corresponding cDNA was cloned in 1986 (42,43). IL-4 is produced by CD4+ (TH) cells, mast cells, and basophils. It induces CD4+ T cells to differentiate into TH2 cells while suppressing the development of TH1 cells. It also acts as a B cell, T cell, and mast cell growth factor, it enhances class II MHC expression on B cells, and it promotes immunoglobulin class switching to IgG1 and IgE (42,43) (Figure 2). In fact, IL-4 is necessary for IgE response induction, and its absence also leads to significantly lower levels of IgG1 in T cell-dependent immune responses (44). The stimulatory effects of IL-4 on IgG1 and IgE production and on MHC class II induction are downregulated by IFN-gamma, a cytokine whose functions are antagonized by IL-4 and vice versa. IL-4 also stimulates collagen (45) and IL-6 production (46) by human dermal fibroblasts, and may thus play a role in the pathogenesis of fibrotic diseases such as systemic sclerosis. In rheumatoid arthritis, on the other hand, IL-4 appears to exhibit some anti-inflammatory properties by inhibiting the production of several pro-inflammatory cytokines such as IL-1, IL-6, IL-8, and TNF-alpha, by synovial membranes of rheumatoid arthritis patients (47).
Cloned in 1987, the IL-5 cDNA encodes a protein of 20-22 kDa which has an apparent molecular weight of 45 kDa upon dimerization. Like IL-4, the gene for IL-5 has also been mapped to chromosome 5 in humans (43). IL-5, also known as B cell growth factor II (BCGFII) and T cell replacing factor (TRF), is produced by CD4+ T helper cells as well as NK cells, and exists as a dimer linked by disulfide bonds (40). IL-5 is involved in eosinophil differentiation and activation and stimulation of immunoglobulin class switching to IgA. Other properties of IL-5 include increased activation of B cell proliferation, and enhancement of T cell cytotoxicity (43). The combined production of IL-4 and IL-5 by CD4+ TH2 cells therefore results in IgE and IgA production and mast cell and eosinophil stimulation.
IL-7 is a cytokine of about 25 kDa whose cDNA was cloned in 1989. Its gene has been mapped to human chromosome 8 (48). IL-7, a cytokine purified as a pre-B cell growth factor, is a bone marrow and thymic stromal cell product. It stimulates the development of pre-B and pre-T cells and acts as a growth factor for B cells, T cells, and early thymocytes (48) (Figure 2).
IL-9 is another cytokine produced by CD4+ T helper (TH2) cells as well as some B lymphomas. First described in the mouse, IL-9 was known as mast cell growth-enhancing activity (MEA) and murine T-cell growth factor P40 (49). The IL-9 cDNA was cloned in 1989 (50) and the gene encoding it was mapped to human chromosome 5 (51). Its production is IL-4 and IL-10, and thus IL-2-dependent. IL-9 is regulatory in nature in that it inhibits lymphokine production by IFN-gamma-producing CD4+ T cells and enhances the growth of CD8+ T cells (52). In addition, IL-9 promotes the production of immunoglobulins by B cells and the proliferation of mast cells (53).
IL-10 is also referred to as B cell-derived T cell growth factor and cytokine synthesis inhibitory factor (CSIF) because it inhibits IFN-gamma production by activated T cells. The cDNA for human IL-10 was cloned in 1990 and found to encode an 18 kDa protein. IL-10 is produced by a variety of cell types, including CD4+ T cells, activated CD8+ T cells, and activated B cells (54). Its effects include reduction of antigen-specific T cell proliferation, inhibition of IL-2-induced IFN-gamma production by NK cells, and inhibition of IL-4 and IFN-gamma induced MHC class II expression on monocytes (55). Since IL-10 can be produced by TH2 cells and inhibits TH1 function by preventing TH1 cytokine production (such as IFN-gamma), IL-10 is considered a T cell cross-regulatory factor and has thus been referred to as an "anticytokine" (56). IL-10 also acts as a co-differentiation factor for cytotoxic T cells and a co-factor for T cell growth. Human IL-10 (hIL-10) shares 84% identity at the amino acid level with a homolog, viral IL-10 (vIL-10), which is encoded by the Epstein-Barr virus (57). vIL-10 shares with hIL-10 inhibitory effects on cytokine production and stimulatory effects on B cell growth (58).
IL-13 was originally identified as a protein produced by activated murine TH2 lymphocytes and referred to as P600 (59). The cDNA for IL-13 was recently cloned and the gene was mapped to human chromosome 5, closely linked to the gene encoding IL-4 (60). A 12-17 kDa protein, IL-13 exhibits anti-inflammatory activities by inhibiting the production of inflammatory cytokines, such as IL-1ß, TNF-alpha, IL-8, and IL-6, by human peripheral blood monocytes induced with lipopolysaccharide (60). Inhibition of inflammatory cytokine production is also a characteristic of two other cytokines produced by TH2 lymphocytes, namely IL-4 and IL-10. In addition, IL-13 enhances monocyte and B lymphocyte differentiation and proliferation, increases CD23 expression, and induces IgG4 and IgE class switching (61).
A product of malignant B and T cells as well as normal T cells, IL-14 is a 53 kDa B-cell growth factor (BCGF). Like IL-4, IL-14 has been shown to induce B cell proliferation. However, IL-14 inhibits immunoglobulin secretion (53). It has been suggested to play an important role in the aggressive form of B-cell type non-Hodgkin's lymphoma (62).
4.1.1.9 Transforming growth factor-ß:
The transforming growth factor-ß(TGF-ß) family of cytokines includes three isoforms, TGF-ß1, ß2, and ß3 which are encoded by separate genes yet bind to the same high affinity receptor. TGF-ß functions as a 25 kDa homodimer consisting of two 12-kDa polypeptides (63). The human cDNA for TGF-ß1 was cloned in 1985 (64). It is produced by T cells, platelets, and monocytes. TGF-ß inhibits T cell and NK cell proliferation and activation (Figure 2) and may play an important role in inflammation (64). At a site of injury, TGF-ß stored in platelets is released upon degranulation. TGF-ß then attracts monocytes and other leukocytes to the site, thus participating in the initial step of chronic inflammation. TGF-ß then positively regulates its own production and the production and deposition of extracellular matrix components as well as the expression of integrins resulting in enhanced cell adhesion. It also inhibits collagenase production, and if expression is prolonged, it may result in progressive fibrosis analogous to unregulated tissue repair. Conditions in which a role for TGF-ß has been suggested include mesangial proliferative glomerulonephritis and diabetic nephropathy in rats, pulmonary fibrosis, and systemic sclerosis (63). Another example of the role played by TGF-ß in inflammation is collagen-induced arthritis in rats. In this model, TNF-alpha and TGF-ß, when injected into the rat ankle joint, accelerate disease onset (65).
4.1.2 Cytokines involved primarily in the cellular inflammatory response:
The human IL-2 cDNA was cloned in 1983 and the corresponding gene has been mapped to the long arm of chromosome 4 (66). IL-2 is a 15 kDa glycoprotein originally known as T cell growth factor (TCGF). It is secreted mainly by activated T helper cells. It acts as a growth factor/activator for T cells, NK cells, and B cells and promotes the development of lymphokine-activated killer (LAK) cells (40,53) (Figure 2). It therefore plays a critical role in regulating both cellular and humoral chronic inflammatory responses. Binding of IL-2 to the IL-2 receptor on T lymphocytes leads to cell proliferation, increased lymphokine secretion (IFN-gamma, lymphotoxin, IL-4, IL-3, IL-5, GM-CSF), and enhanced expression of class II MHC molecules.
IL-12, previously known as natural killer cell stimulatory factor (NKSF) and cytotoxic lymphocyte maturation factor (CLMF), was originally isolated from Epstein-Barr virus transformed B cells. It is a heterodimer composed of two subunits of 35 and 40 kDa. The cDNAs for both subunits were cloned in 1991 (67). Its biological activities include enhancement of cytotoxic T cells and lymphokine-activated killer (LAK) cell generation and activation, increased natural killer (NK) cell cytotoxicity, induction of activated T cell and NK cell proliferation, induction of IFN-gamma production by NK cells and T cells, and inhibition of IgE synthesis by IL-4-stimulated lymphocytes via IFN-gamma-dependent and independent mechanisms (67-69) (Figure 2). IL-12 is secreted by activated B cells, macrophages, and other antigen-presenting cells (APCs), but its production is inhibited by IL-4 and IL-10. In addition, the stimulatory effect of IL-12 on TH1 development is antagonized by IL-4, a cytokine which promotes TH2 cell development. Therefore, IL-12 plays an important role in cell-mediated inflammation and also contributes to the regulation of immunoglobulin production.
IL-15 is a cytokine of approximately 15 kDa originally discovered as a T cell stimulatory activity (70) produced by activated monocytes, epithelial cells, and fibroblasts. IL-15 shares many biologic properties with IL-2 and mediates its activity via a multi-subunit high affinity receptor comprised of a unique alpha chain and the beta and gamma chains of the IL-2R. The human IL-15 gene has been mapped to chromosome 4 (70), similarly to IL-2. However, IL-15 does not exhibit any sequence homology with IL-2. IL-15 is produced by a large variety of cells including T lymphocytes and monocytes. It stimulates T lymphocyte and NK cell proliferation, as well as CTL and LAK activity (53). It enhances B cell expansion and immunoglobulin production (71) (Figure 2). It is also a T lymphocyte chemoattractant. IL-15 may be responsible for the recruitment and activation of T lymphocytes in the synovium of patients with rheumatoid arthritis where its levels have been found to be elevated (72).
The interferons are a group of cytokines originally identified by and named for their anti-viral activity (73). Their corresponding cDNAs were cloned in 1980-81. Type I interferons include IFN-alpha, an 18-20 kDa product of leukocytes, and IFN-ß, a product of fibroblasts. They exhibit anti-viral as well as anti-proliferative properties and upregulate MHC class I expression. IFN-alpha is encoded by several genes clustered in the short arm of chromosome 9. However, only one gene, also localized to chromosome 9, codes for IFN-ß. Type II interferon, immune interferon or IFN-gamma, is a homodimer produced by activated T cells and NK cells. A single gene located on chromosome 12 encodes human IFN-gamma which has a molecular weight of 20 or 25 kDa (monomer) depending on the extent of glycosylation (74). IFN-gamma is known to enhance MHC class I and II expression on nucleated cells and to stimulate many of the effector functions of mononuclear phagocytes. While IFN-alpha and -ß bind to a common receptor, IFN-gamma recognizes a distinct and specific cell surface receptor. IFN-gamma has been implicated in the pathogenesis of a variety of autoimmune and chronic inflammatory conditions (75) including murine models of systemic lupus erythematosus (76), Type I diabetes mellitus (77,78), adjuvant-induced arthritis (79), and experimental cerebral malaria (80). Based on experiments with IFN-gamma knock-out mice, one of its primary functions in vivo appears to be the activation of macrophages to kill intracellular pathogens such as Mycobacteria (81).
4.1.2.5 IFN-gamma-inducing factor:
An IFN-gamma-inducing activity was identified in murine Kupffer cells and activated macrophages and referred to as IFN-gamma-inducing factor (IGIF) (82). IGIF induces IFN-gamma production more potently than does IL-12 and is involved in the development of TH1 cells. The human homolog has been recently described and shares functions with the murine cytokine such as the induction of IFN-gamma production by stimulated PBMC and the enhancement of NK cell cytotoxicity (83). In addition, human IGIF augments GM-CSF production and decreases IL-10 production. It has been proposed that IGIF be designated as Interleukin-18 (IL-18) (83).