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 immune-inflammatory diseases such as rheumatoid arthritis (RA). However, the discovery of a biologically active monokine of similar to 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 metaIIoproteinases (MMP) by fibrobiasts, 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. Another, more specific, inhibitory mechanism involves molecules that act as true receptor antagonists such as the IL-1 receptor antagonist (IL-1Ra) or as proteins binding to the ligand, many of them being soluble inhibitory fragments derived from the extracellular domain of the two receptors for TNF (TNF-sR55 and TNF-sR75) or the two receptors for IL-1 (IL-1sRI and IL-1sRII). Both IL-1Ra and TNF-sR, initially observed in our laboratory in their natural form in the serum of highly febrile patients or of those with monocytic leukemia, have been cloned by different investigators and their efficacy is being assessed in clinical tests set up for various pathologies, in particular sepsis, allergic diseases and RA. It is to be hoped that the inhibition of biological activities and production of IL-I acid TNF-a provides a pharmacological approach that will help to prevent the destruction of connective tissue and that will not almost exclusively consist of anti-inflammatory and painkilling effects.