Inflammation is an important homeostatic mechanism that limits the effects of infectious agents. However, inflammation might be self-damaging and therefore has to be tightly controlled or even abolished by the organism. Interleukin 1 (IL-1) is a critical mediator of the inflammatory response, playing an important part in the development of pathologic conditions leading to chronic inflammation. Although IL-1 production may be downmodulated or its effect limited by so-called anti-inflammatory cytokines. IL-1 inflammatory effects are inhibited and can be abolished (in vitro) by one particularly powerful inhibitor. IL-1 receptor antagonist (IL-lRa).
To date, three forms of IL-lRa have been identified, one soluble form and two intracellular forms, referred to as sIL-lRa. icIL-lRal. and icIL-lRall. respectively. Although sIL-IRa functions obviously as an IL-1 inhibitor by competitively binding to IL-1 receptor without inducing signal transduction, the functions of icIL-lRal and icIL-lRall remain to be determined. The three forms of IL-lRa are transcribed from the same gene, two different promoters regulating the transcription of sIL-IRa and icIL-lRal. In mice. sIL-IRa is predominantly found in peripheral blood cells, the lung, spleen, and liver, while icIL-lRal is mainly found in the skin. IL-lRa knockout mice display growth retardation after weaning and an increased susceptibility to endotoxin-induced injury and collagen-induced arthritis, suggesting that IL-IRa plays an important part in both health and pathologic conditions. IL-IRa is produced by hepatic cells as an acute phase protein. The circulating blood levels of sIL-IRa are low in normal condition and elevated in individuals with allele 2 polymorphism and in several human infectious, autoimmune, and chronic inflammatory diseases, as well as in numerous experimental models of diseases in animals. Because of its beneficial effects in many animal disease models. IL-IRa has been used as therapeutic agent in human patients. IL-IRa has failed to show beneficial effects in septic shock but seems to improve the condition of rheumatoid arthritis patients.