INTERLEUKIN-1 AND INTERLEUKIN-1 RECEPTOR ANTAGONIST

Cytokines are produced in disease or during immunologic challenge. Som e cytokines increase host resistance to disease whereas others trigger inflammatory processes, Interleukin 1 (IL-1) and tumor necrosis facto r (TNF) are pro-inflammatory cytokines that affect nearly every cell e ither alone or in a synergistic fashion. TNF animal models of infectio us, inflammatory or metastatic disease, the role of IL-1 and TNF has b een defined by specifically blocking these cytokines. For TNF, anti-TN F monoclonal antibodies and soluble receptors reduce inflammation and lethality. Antibodies to type I IL receptor, IL-1 receptor antagonist (IL-1(ra)), and soluble IL-1 receptor have been used to reduce the sev erity of disease in various animal models of local and systemic inflam mation. In a Phase III trial, IL-1(ra) reduced mortality rate in patie nts with septic shock syndrome by 22%. IL-1(ra) and soluble receptors to TNF are produced naturally and are elevated in the circulation in s everal diseases. It is unclear whether these endogenous levels are suf ficient to block IL-1 and TNF from triggering their respective cell-bo und receptors in disease. IL-1 infusions into patients induce circulat ing levels of IL-1(ra) but not IL-1. TNF infusions into patients also induce high levels of soluble TNF receptors.