Production of mice deficient in genes for interleukin (IL)-1α, IL-1β, IL-1α/β, and IL-1 receptor antagonist shows that IL-1β is crucial in turpentine-induced fever development and glucocorticoid secretion

Interleukin (IL)-1 is a major mediator of inflammation and exerts pleiotropic effects on the neuro-immuno-endocrine system. To elucidate pathophysiological roles of IL-1, we have first produced IL-1 alpha/beta doubly deficient (KO) mice together with mice deficient in either the IL-1 alpha, IL-1 beta, or IL-1 receptor antagonist (IL-1ra) genes. These mice were born healthy, and their growth was normal except for IL-1ra KO mice, which showed growth retardation after weaning. Fever development upon injection with turpentine was suppressed in IL-1 beta as well as IL-1 alpha/beta KO mice, but not in IL-1 alpha KO mice, whereas IL-1ra KO mice showed an elevated response. At this time, expression of IL-1 beta mRNA in the diencephalon decreased 1.5-fold in IL-1 alpha KO mice, whereas expression of IL-1 alpha mRNA decreased >30-fold in IL-1 beta KO mice, suggesting mutual induction between IL-1 alpha and IL-1 beta. This mutual induction was also suggested in peritoneal macrophages stimulated with lipopolysaccharide in vitro. In IL-1 beta KO mice treated with turpentine, the induction of cyclooxygenase-2 (EC 1.14.99.1) in the diencephalon was suppressed, whereas it was enhanced in IL-1ra KO mice. We also found that glucocorticoid induction 8 h after turpentine treatment was suppressed in IL-1 beta but not IL-1 alpha KO mice. These observations suggest that IL-1 beta but not IL-1 alpha is crucial in febrile and neuro-immuno-endocrine responses, and that this is because IL-1 alpha expression in the brain is dependent on IL-1 beta. The importance of IL-1ra both in normal physiology and under stress is also suggested.