The interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring molecule that shares homology with IL-1alpha and IL-1beta. It binds competitively to IL-1 receptors type I and type II with the same affinity as does IL-1, but does not induce any intracellular response. Two structural variants of IL-1Ra have been described: a 17 kDa form that is secreted from monocytes, macrophages, neutrophils, and other cells (sIL-1Ra) and an 18- kDa form that remains in the cytoplasm of keratinocytes and other epithelial cells, monocytes, and fibroblasts (icIL-1Ra). An additional 16- kDa intracellular isoform of IL-1Ra has been described in neutrophils, monocytes, and hepatic cells. Both of the major isoforms of IL-1Ra are transcribed from the same gene through the use of alternative first exons. The production of IL-1Ra is stimulated by many substances including adherent IgG, other cytokines, and bacterial or viral components. The tissue distribution of IL-1Ra in mice indicates that sIL-1Ra is found predominantly in peripheral blood cells, lung, 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 defence 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 inflammatory diseases. The use of neutralizing anti-IL-1Ra antibodies has demonstrated that endogenous IL-1Ra is an important natural antiinflammatory protein in arthritis, colitis, and granulomatous pulmonary disease.Synonyms: ICIL-1RA, IL-1RN, IL-1ra, IL1 inhibitor, IL1F3, IRAP, Interleukin-1 receptor antagonist protein