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Production of Mice Deficient in Genes for Interleukin (IL)-1, IL-1β, IL-1/β, and IL-1 Receptor Antagonist Shows that IL-1β Is Crucial in Turpentine-induced Fever Development and Glucocorticoid Secretion

Reiko Horai^*, Masahide Asano^*, Katsuko Sudo^*, Hirotaka Kanuka, Masatoshi Suzuki, Masugi Nishihara, Michio Takahashi, and Yoichiro Iwakura^*

From the ^* Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108, Japan; and Veterinary Medical Science, University of Tokyo, Bunkyo-ku, Tokyo 113, Japan

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/β doubly deficient (KO) mice together with mice deficient in either the IL-1, IL-1β, 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-1β as well as IL-1/β KO mice, but not in IL-1 KO mice, whereas IL-1ra KO mice showed an elevated response. At this time, expression of IL-1β mRNA in the diencephalon decreased 1.5-fold in IL-1 KO mice, whereas expression of IL-1 mRNA decreased >30-fold in IL-1β KO mice, suggesting mutual induction between IL-1 and IL-1β. This mutual induction was also suggested in peritoneal macrophages stimulated with lipopolysaccharide in vitro. In IL-1β 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-1β but not IL-1 KO mice. These observations suggest that IL-1β but not IL-1 is crucial in febrile and neuro-immuno-endocrine responses, and that this is because IL-1 expression in the brain is dependent on IL-1β. The importance of IL-1ra both in normal physiology and under stress is also suggested.

² Asano, M., R. Horai, and Y. Iwakura, manuscript in preparation.

Abbreviations used: ACTH, adrenocorticotropic hormone; COX, cyclooxygenase; CRH, corticotropin-releasing hormone; DT, diphtheria toxin A fragment gene; ES, embryonic stem; HPA, hypothalamic-pituitary-adrenal; IL-1RI and IL-1RII, IL-1 type I and II receptors; IL-1ra, IL-1 receptor antagonist; KO, knockout; PEC, peritoneal exudate cells; PGK, phosphoglycerate kinase.

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