Cytokine imbalance in the pathogenesis of rheumatoid arthritis: The role of interleukin-1 receptor antagonist

Objectives: To summarize the role of cytokine imbalance in the pathogenesis of rheumatoid arthritis. Methods: The literature on cytokines in rheumatoid arthritis from American and European medical journals was reviewed. Results: An important role of interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha in the mediation of tissue damage in the rheumatoid joint has b een well established over the past 10 years. The IL-1 family consists of 2 agonists, IL-1 alpha and IL-1 beta, and a specific naturally occurring rece ptor antagonist, IL-1Ra. Both forms of IL-1 induce intracellular responses through binding to the type 1 IL-1 receptor (IL-1R) on target cells. IL-1Ra binds to IL-1R with an avidity equal to that of IL-1 but fails to stimulat e the cells, thus functioning as an inhibitor of IL-1 binding. Endogenous p roduction of IL-1Ra is an important anti-inflammatory mechanism both in ani mal models of disease and in human disease. In the rheumatoid synovium, an imbalance exists in this system, because the relative levels of production of IL-1Ra are not adequate to effectively block the proinflammatory effects of IL-1. Studies in different animal models of inflammatory arthritis indi cate that a deficiency of IL-1Ra relative to IL-1 leads to more severe dise ase and even to the spontaneous development of arthritis as observed in IL- 1Ra knockout mice. A restoration of the balance between IL-1Ra and IL-1 in human disease can theoretically be achieved through the administration of r ecombinant IL-1ra protein, gene therapy with the IL-1Ra complementary DNA, or stimulation of production of endogenous IL-1Ra. Conclusions: An imbalance between proinflammatory cytokines and cytokine an tagonists or inhibitors may be one factor predisposing to initiation or per petuation of rheumatoid synovitis. Semin Arthritis Rheum 30:1-6 (Suppl 2). Copyright (C) 2001 by W.B. Saunders Company.