Cytokines rheumatoid arthritis

Chabaud M, Garnero P, Dayer JM, Guerne PA, Fossiez F, Miossec P Contribution of interleukin 17 to synovium matrix destruction in rheumatoid arthritis. Cytokine 2000 12 1092-1099. 

Miossec P (2004) An update on the cytokine network in rheumatoid arthritis. Curr Opin Rheumatol 16 218-222... 

IFN- 3 reduces the induction by inflammatory cytokines of adhesion molecules and of MHC class I and II complex on endothelial cells, a process preceding attachment and transendothelial migration of T-cells. These anti-inflammatory effects of IFN- 3 exemplify antagonistic actions of type I and type IIIFN. There is, indeed, much clinical evidence for the involvement of IFN-y in inflammatory processes - through activation of iNOS and subsequent secretion of NO - leading to the establishment of autoimmune diseases as for instance in rheumatoid arthritis. 

Rheumatoid Arthritis. Figure 2 The concept of a cytokine dysequilibrium. Many cytokines are detectable in rheumatoid synovial tissues, including those with predominantly anti-inflammatory properties. But the net effect is a dominance of proinflammatory activity. 

Human tumor necrosis factor (TNF) (Fig. 1) is a hormone-like proinflammatory peptide belonging to the group of cytokines. It is mainly produced by cells of the immune system in response to infection, inflammation, or cell damage. Disregulated TNF is an important factor in many pathological situations, like sqDsis, rheumatoid arthritis, inflammatory bowel disease (Crohn s disease), and Cachexia. The cytotoxic activity of TNF is of interest in development of new antitumoral strategies. 

TNF is a pleiotropic cytokine exerting a wide range of cellular responses, that affect biological processes such as lipid metabolism, coagulation, and insulin resistance and the function of endothelial cells. As a major proinflammatory cytokine TNF is also involved in progression of diseases like cancer, Alzheimer, Diabetes type II, cardiovascular, pulmonary or neurological disorders, and many autoimmune diseases. Blocking the action of TNF clearly reduces its inflammatory potential on various autoimmune disorders like Crohn s disease, rheumatoid arthritis (RA), and psoriasis. 

Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001 344( 12) 907—916. Cronstein BN. Low-dose methotrexate A mainstay in the treatment of rheumatoid arthritis. Pharmcol Rev 2005 57(2) 163—172. 

Koch AE, Kunkel SL, Harlow LA, et al. Macrophage inflammatory protein-1 alpha. A novel chemotactic cytokine for macrophages in rheumatoid arthritis. J Clin Invest 1994 93(3) 921-928. 

Chabaud M, Page G, Miossec P. Enhancing effect of IL-1, IL-17, and TNF-alpha on macrophage inflammatory protein-3alpha production in rheumatoid arthritis regulation by soluble receptors and Th2 cytokines. J Immunol 2001 167(10) 6015-6020. 

Blaschke S, Middel P, Domer BG, et al. Expression of activation-induced, T cell-derived, and chemokine-related cytokine/lymphotactin and its functional role in rheumatoid arthritis. Arthritis Rheum 2003 48(7) 1858-1872. 

Nanki T, Imai T, Nagasaka K, et al. Migration of CX3CR1-positive T cells producing type 1 cytokines and cytotoxic molecules into the synovium of patients with rheumatoid arthritis. Arthritis Rheum 2002 46(ll) 2878-2883. 

Glycoproteins similar to the IDGFs are found in mammals and may constitute a novel class of cytokines, some of which are important in inflammation. The best characterized is the human glycoprotein HC gp-39 (= YKL40 16-23% identical to IDGFs), which accumulates in the synovial fluid of rheumatoid arthritis... 

Mclnnes, I. and Liew, F. (2005) Cytokine networks - towards new therapies for rheumatoid arthritis. Nature Clinical Practice Rheumatology 1(1), 31-39. 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

Interleukin 1 (IL-1) is produced mainly by activated monocytes-macropha-ges, and its principal action is to stimulate thymocytes. A pleiotropic cytokine, IL-1 induces the expression of a large diversity of cytokines such as IL-6, leukaemia inhibitory factor (LIF), and other proinflammatory molecules (Di-marello 1994). IL-1 and TNF-a carry out as part of their function increasing the expression of NF-/cB and JNK (c-Jun N-terminal kinase). The importance of IL-1 in OCS is demonstrated because the IL-1-receptor-deficient mouse is resistant to ovariectomy (OVX)-induced bone loss (Lorenzo et al. 1998). The importance in pathological bone loss is also illustrated by the fact that treatment with IL-1 receptor antagonist slows down bone erosion for patients affected with rheumatoid arthritis (Kwan et al. 2004). IL-1 increases osteoclast differentiation rather than mature osteoclast activity, and infusion of IL-1 into mice induces hypercalcemia and bone resorption. Finally, IL-1 and TNF-a... 

Alvaro-Gracia, J. M., Zvaifler, N. J., Brown, C. B., Kaushansky, K., Firestein, G. S. (1991). Cytokines in chronic inflammatory arthritis VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-a J. Immunol 146,3365-71. 

Arend, W. P., Dayer, J.-M. (1990). Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthrit. Rheum. 33,305-15. 

Two more recent studies have also addressed SNP polymorphisms and potential links to clinically relevant conditions. " Given the role in inflammation and cytokine expression, one study examined the potential for linkage to autoimmune diseases including type 1 diabetes, rheumatoid arthritis, and inflammatory bowel disease in a population of more than 2000 patients. No significant association was found with any of the SNPs. In contrast, a strong association was found between a single polymorphism (G-105A alteration in the promoter) and women with preeclampsia. " Women who had preeclampsia were 1.34 times more likely to carry this mutant allele. The role that this mutant plays in the condition is unknown. 

A variety of medical conditions are now believed to be caused or exacerbated by overproduction of certain cytokines in the body. A variety of pro-inflammatory cytokines, including IL-6 and IL-8 as well as TNF, have been implicated in the pathogenesis of both septic shock and rheumatoid arthritis. Inhibiting the biological activity of such cytokines may provide effective therapies for such conditions. This may be achieved by administration of monoclonal antibodies raised against the target cytokine, or administration of soluble forms of its receptor which will compete with cell surface receptors for cytokine binding. 

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