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Role of cytokines in rheumatic diseases

Iain B McInnes, FRCP, PhD
Section Editor
Daniel E Furst, MD
Deputy Editor
Paul L Romain, MD


Cytokines are proteins that regulate the immune system and that participate in intercellular communications. A complex cytokine network is involved in normal immune function, and this network is comprised of positive and negative feedback loops that enhance or suppress the response. Many immune-mediated diseases (especially rheumatic diseases) involve the abnormal regulation of cytokines (table 1). This can be manifested either by defective production of suppressive factors or by overproduction of proinflammatory cytokines (figure 1). As a result, understanding cytokine regulation abnormalities in these diseases could ultimately lead to novel and specific treatments. (See "Cytokine networks in rheumatic diseases: Implications for therapy" and "Overview of biologic agents and kinase inhibitors in the rheumatic diseases".)

Issues relating to the role of cytokines in rheumatic diseases are reviewed here. Overviews of the effects of cytokines on the immune response and the therapeutic implications of cytokine networks in rheumatic disease are presented separately. (See "Role of cytokines in the immune system" and "Cytokine networks in rheumatic diseases: Implications for therapy".)


There is more information on the role of cytokines in rheumatoid arthritis (RA) than in any other rheumatic disease. In addition, these studies have led to clinical trials with several novel agents designed to interrupt the cytokine network of RA. Anticytokine therapy has shown clear evidence of clinical efficacy, especially with tumor necrosis factor (TNF)-alpha directed approaches. In general, T cell-derived factors are not as prominent as macrophage and fibroblast cytokines in the rheumatoid joint.

T cell cytokines — Interferon (IFN)-gamma was the initial target of cytokine research in RA. This was due, in part, to the availability of sensitive IFN bioassays. The synovial fluid of patients with RA demonstrated IFN-like activity using viral cytopathic inhibition assays, which take advantage of the fact that interferons protect cells from viral infection [1]. The presence of human leukocyte antigen (HLA)-DR expression in RA synovium also suggested the presence of IFN-gamma, since this cytokine was the most potent DR inducer known. These observations, along with later studies demonstrating putative interleukin (IL)-2 activity in synovial effusions [2] and the presence of T-cell surface markers associated with activation (major histocompatibility complex [MHC] DR+, VLA4+, CD69+), tended to support the hypothesis that the T cells in RA were highly activated and that the local milieu contained significant concentrations of T cell derived cytokines.

Subsequently, however, this view had to be reconsidered when specific immunoassays demonstrated only limited amounts of IFN-gamma in RA joints, far below that typically required to induce HLA-DR expression [3]. The IFN-like activity that was detected in joints was actually due to non-IFN factors (demonstrating the vagaries of bioassays).


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Literature review current through: Sep 2016. | This topic last updated: Jan 2, 2016.
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