[Cytokines and anti-cytokines in inflammatory rheumatism]

Studies done over the last few years have demonstrated that interleukin-1 and tumor necrosis factor alpha, which are produced mainly by monocyte-macrophages, are the key mediators of inflammation and tissue destruction in rheumatoid arthritis. The synergistic effects of these factors lead to the production of large amounts of metalloproteases by the synovial cells, chondrocytes, and bone-derived cells. Direct membrane-to-membrane contact between activated lymphocytes and monocyte-macrophages is one of the main factors activating the production of interleukin-1 and tumor necrosis factor alpha. This activation involves several glycoproteins expressed at the surface of activated lymphocytes (CD11, CD69). Antibodies can partially block this lymphocyte-monocyte interaction. Recent studies have identified two mechanisms capable of inhibiting macrophage and synovial cell activation. One calls into play the antiinflammatory cytokines, such as interleukin-4 and interleukin-10, which are potent inhibitors of the production of interleukin-1, tumor necrosis factor alpha, and the metalloproteases. Interleukin-10 also activates the tissue inhibitor of metalloproteases. The second mechanism, which is more specific, involves antagonists such as the interleukin-1 receptor antagonist and inhibitory soluble fragments derived from the extramembranous portion of the two receptors for tumor necrosis factor alpha (TNF-sR55 and TNF-sR75). These molecules, which we first studied in their naturally-occurring form, have been cloned and are being tested in several conditions including rheumatoid arthritis. Similar soluble fragments of the receptors for interleukin-1 alpha and beta can inhibit interleukin-1.(ABSTRACT TRUNCATED AT 250 WORDS)