INTERLEUKIN-1 RECEPTOR ANTAGONIST - ROLE IN BIOLOGY

The interleukin-l receptor antagonist (IL-1Ra) is a member of the IL-1 family that binds to IL-1 receptors but does not induce any intracell ular response. Two structural variants of IL-1Ra have previously been described: a 17-kDa form that is secreted from monocytes, macrophages, neutrophils, and other cells (sIL-1Ra) and an 18-kDa form that remain s in the cytoplasm of keratinocytes and other epithelial cells, monocy tes, and fibroblasts (icIL-1Ra). An additional 16-kDa intracellular is oform of IL-1Ra has recently been described in neutrophils, monocytes, and hepatic cells. Both of the major isoforms of IL-1Ra are transcrib ed from the same gene through the use of alternative first exons. The two promoters regulating transcription of the secreted and intracellul ar forms have been cloned, and some of the functional cis-acting DNA r egions have been characterized. The production of IL-1Ra is stimulated by many substances including adherent IgG, other cytokines, and bacte rial or viral components. The tissue distribution of IL-1Ra in mice in dicates that sIL-1Ra is found predominantly in peripheral blood cells, lungs, spleen, and liver, while icIL-1Ra is found in large amounts in skin. Studies in transgenic and knockout mice indicate that IL-1Ra is important in host defense against endotoxin-induced injury. IL-1Ra is produced by hepatic cells with the characteristics of an acute phase protein. Endogenous IL-1Ra is produced in numerous experimental animal models of disease as well as in human autoimmune and chronic inflamma tory diseases. The use of neutralizing anti-IL-1Ra antibodies has demo nstrated that endogenous IL-1Ra is an important natural antiinflammato ry protein in arthritis, colitis, and granulomatous pulmonary disease. Treatment of human diseases with recombinant human IL-1Ra showed an a bsence of benefit in sepsis syndrome. However, patients with rheumatoi d arthritis treated with IL-1Ra for six months exhibited improvements in clinical parameters and in radiographic evidence of joint damage.