title: Production of mice deficient in genes for interleukin (IL)-1alpha, IL-1beta, IL-1alpha/beta, and IL-1 receptor antagonist shows that IL-1beta is crucial in turpentine-induced fever development and glucocorticoid secretion.
abstract: 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-1alpha/beta doubly deficient (KO) mice together with mice deficient in either the IL-1alpha, IL-1beta, 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-1beta as well as IL-1alpha/beta KO mice, but not in IL-1alpha KO mice, whereas IL-1ra KO mice showed an elevated response. At this time, expression of IL-1beta mRNA in the diencephalon decreased 1.5-fold in IL-1alpha KO mice, whereas expression of IL-1alpha mRNA decreased >30-fold in IL-1beta KO mice, suggesting mutual induction between IL-1alpha and IL-1beta. This mutual induction was also suggested in peritoneal macrophages stimulated with lipopolysaccharide in vitro. In IL-1beta 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-1beta but not IL-1alpha KO mice. These observations suggest that IL-1beta but not IL-1alpha is crucial in febrile and neuro-immuno-endocrine responses, and that this is because IL-1alpha expression in the brain is dependent on IL-1beta. The importance of IL-1ra both in normal physiology and under stress is also suggested.
authors.affiliation: Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Horai
authors.forename: M
authors.initials: M
authors.lastname: Asano
authors.forename: K
authors.initials: K
authors.lastname: Sudo
authors.forename: H
authors.initials: H
authors.lastname: Kanuka
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Nishihara
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: Y
authors.initials: Y
authors.lastname: Iwakura
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology; D005938:Glucocorticoids / Q000378:metabolism*; D007249:Inflammation / Q000503:physiopathology; D007375:Interleukin-1 / Q000235:genetics* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D014425:Turpentine / Q000494:pharmacology*
chemical_list: D005938:Glucocorticoids; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D003345:Corticosterone; D014425:Turpentine