Cytokines in rheumatoid arthritis

Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996 14 397-440. 

Deleuran, B. W. (1996) Cytokines in rheumatoid arthritis. Localization in arthritic joint tissue and regulation in vitro. Scand. J. Immunol 25,1-38. 

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. 

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. 

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. 

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. 

It is a cyclic polypeptide with 11 amino acids. It selectively inhibits T-lymphocytes proliferation, IL-2 and other cytokine production. It is the most effective drug for prevention and treatment of graft rejection reaction. It is used in cardiac, hepatic, renal, bone marrow transplantation and as second line drug in rheumatoid arthritis, inflammatory bowel disease, dermato-myositis, bronchial asthma and certain other autoimmune diseases. 

Sulfasalazine is metabolized to sulfapyridine and 5-aminosalicylic acid, and it is thought that the sulfapyridine is probably the active moiety when treating rheumatoid arthritis (unlike inflammatory bowel disease, see Chapter 62). Some authorities believe that the parent compound, sulfasalazine, also has an effect. In treated arthritis patients, IgA and IgM rheumatoid factor production are decreased. Suppression ofT-cell responses to concanavalin and inhibition of in vitro -cell proliferation have also been documented. In vitro studies have shown that sulfasalazine or its metabolites inhibit the release of inflammatory cytokines, including those produced by monocytes or macrophages, eg, interleukins-1, -6, and -12, and TNF-a. These findings suggest a possible mechanism for the clinical efficacy of sulfasalazine in rheumatoid arthritis. 

Cytokines play a central role in the immune response (see Chapter 56) and in rheumatoid arthritis. Although a wide range of cytokines are expressed in the joints of rheumatoid arthritis patients, TNF-a appears to be particularly important in the inflammatory process. 

Charles P et al Regulation of cytokines, cytokine inhibitors, and acute-phase proteins following anti-TNF-a therapy in rheumatoid arthritis. J Immunol 1999 163 1521. [PMID 10415055]... 

IL-18 augments T- and NK-cell maturation, cytotoxicity and cytokine production. It stimulates TH differentiation, promotes secretion of TNF-a, IFN-y and GM-CSF and enhances NK cell cytotoxicity by increasing FasL expression. IL-8-mediated neutrophil chemotaxis is promoted by IL-18 via its effects on TNF-a and IFN-y, which are stimulatory in action. It plays an important role in maintaining synovial inflammation and inducing joint destruction in rheumatoid arthritis. In synovium of patients with rheumatoid arthritis, enhanced levels of TNF-a and IL-1 are associated with augmented expression of IL-18. 

Choy EH, Pnaayi GS. 2001. Cytokine pathways and joint inflammation in rheumatoid arthritis. NEJM. 344 907-916. 

In addition to direct effects on genes regulating inflammation, glucocorticoids also inhibit the transcription factors that initiate synthesis of pro-inflammatory cytokines (e.g., interleukin-1, tumor necrosis factor), enzymes (e.g., COX-2, nitric oxide synthase), and receptor proteins (e.g., natural killer receptors).17,87,89 Glucocorticoids may also exert some of their effects via a membrane-bound receptor that regulates activity of macrophages, eosinophils, T lymphocytes, and several other types of cells involved in the inflammatory response.89 Consequently, glucocorticoids affect many aspects of inflammation, and their powerful anti-inflammatory effects in rheumatoid arthritis result from their ability to blunt various cellular and chemical components of the inflammatory response. 

Several agents are now available that inhibit the action of tumor necrosis factor-alpha (TNF-a). TNF-a is a small protein (cytokine) that is released from cells involved in the inflammatory response. TNF-a seems to be a key chemical mediator that promotes inflammation and joint erosion in rheumatoid arthritis.83 Drugs that inhibit this chemical will therefore help delay the progression of this disease by decreasing TNF-a s destructive effects.70... 

Anakinra (Kineret) blocks the effects of interleukin-1 on joint tissues. Like TNF-a, interleukin-1 is a cytokine that promotes inflammation and joint destruction in rheumatoid arthritis.23,36 By blocking interleukin-1 receptors on joint tissues, anakinra prevents the destructive events mediated by this cytokine. This drug appears to be moderately effective in limiting the progression of rheumatoid arthritis, and it is generally well tolerated.36 Hence, anakinra is another option that can be used alone or in combination with other DMARDs such as methotrexate.23... 

Steiner, G., Tohidast-Akrad, M., Witzmann, G., Vesely, M., Studnicka-Benke, A., Gal, A., Kunaver, M., Zenz, P., and Smolen, J. S. (1999). Cytokine production by synovial T cells in rheumatoid arthritis. Rheumatology 38, 202-213. 

A small-molecule inhibitor of tumor necrosis factor a, a protein involved in inflammatory diseases such as rheumatoid arthritis, has been identified <2005SCI1022>. Direct inhibition by the commercial biological agents Enbrel and Remicade has produced major advances in rheumatoid arthritis treatment and validated extracellular inhibition of this proinflammatory cytokine as an effective therapy. The new inhibitor 35 is composed of trifluoromethylphenyl indole and dimethylchromone moieties linked by a dimethylethylenediamine spacer. 

Koch AE, Harlow LA, Haines GK, Amento EP, Unemori EN, Wong WL, et al. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol 1994 152 4149-4156. 

CSF, M-CSF, called the autocrine loop). TNF-a and IL-1 are potent upregulators of several cell t) es including fibroblasts and T cells. TNF-a may act earlier in the hierenchy than other cytokines and has proven to be an important target for anticytokine therapy in rheumatoid arthritis and Crohn s disease (see later, anti-TNF therapy). Some small amounts of anti-inflammatory cytokines may also be present (such as IL-10 and interferon-y), but because the system is not in balance, the end result is inflammation. 

New England Journal of Medicine 338 446-452 Choy E H S, Panayi G S 2001 Cytokine pathways cind joint inflammation in rheumatoid arthritis. New England Journal of Medicine 344 907-916 Creamer P, Hochberg M C 1997 Osteoarthritis. Lancet 350 503-509... 

Wylie G, Appelboom T, Bolten W, Breedveld FC, Feely J, Teeming MR, Le Loet X, Manthorpe R, Marcolongo R, Smolen J. A comparative study of tenidap, a cytokine-modulating anti-rheumatic drug, and diclofenac in rheumatoid arthritis a 24-week analysis of a 1-year clinical trial. Br J Rheumatol 1995 34(6) 554-63. 

G6P isomerase (GPI EC 5.3.1.9) (also known as phospho-giucose isomerase [PGI]), catalyzes the interconversion of G6P and fructose 6-phosphate (F6P), the second step of the EMP. As a result of this reversible reaction, products of the hexose monophosphate pathway can be recycled to G6P. Besides being a housekeeping enzyme of glycolysis, GPI exerts outside the cell cytokine properties and is involved in several extracellular processes. In addition, autoantibodies against GPI seem to be involved in rheumatoid arthritis. GPI is a crucial enzyme, since GPI knockout mice die in the embryological state. ... 

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