Interleukin-1, Tumor Necrosis Factor and Their Specific Inhibitors

It has become evident during the past years that interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha), mainly produced by monocyte-macrophages, are the principal mediators of tissue destruction in many immuno-inflammatory diseases such as rheumatoid arthritis (RA). However, the discovery of a biologically active monokine of approximately 17 kD preceded the isolation of IL-1 and TNF-alpha as well as their cloning by more than 16 years. The two latter cytokines induce in synergy the production of high levels of matrix metalloproteinases (MMP) by fibroblasts, synovial cells and chondrocytes. The biological activity of MMP is controlled by tissue inhibitor of MMP (TIMP) which also depends on the presence of cytokines in the microenvironment. One of the principal stimuli of the production of IL-1 and TNF-alpha is the direct contact between the membranes of activated lymphocytes and monocyte-macrophages. Several glycoproteins expressed on the surface of activated lymphocytes (CD11, CD69) are implicated in this activation process and can be partially blocked by their respective antibodies. These prompt the decrease of cytokines and proteases in the lymphocyte/monocyte interaction. In the past few years, two pathways for inhibiting the activation of macrophages, fibroblasts and synovial cells have been elucidated. One of them is due to the action of anti-inflammatory cytokines such as IL-4 and IL-10 which considerably decrease production of IL-1, TNF-alpha and metalloproteases. In contrast to IL-4, IL-10 is also capable of stimulating the production of TIMP.(ABSTRACT TRUNCATED AT 250 WORDS)