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

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-1α/β doubly deficient (KO) mice together with mice deficient in either the IL-1α, 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-1α/β KO mice, but not in IL-1α 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-1α KO mice, whereas expression of IL-1α mRNA decreased >30-fold in IL-1β KO mice, suggesting mutual induction between IL-1α 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-1α KO mice. These observations suggest that IL-1β but not IL-1α is crucial in febrile and neuro-immuno-endocrine responses, and that this is because IL-1α expression in the brain is dependent on IL-1β. The importance of IL-1ra both in normal physiology and under stress is also suggested.

Increased fat:carbohydrate oxidation ratio in Il1ra −/− mice on a high-fat diet is associated with increased sympathetic tone

“…Animals Il1ra −/− mice were produced as described previously [31]. These mice were backcrossed to C57BL/6J mice for nine generations.…”

Suppression of autoimmune arthritis in interleukin‐1‐deficient mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells

“…IL-1␣ Ϫ/Ϫ , IL-1␤ Ϫ/Ϫ , and IL-1␣/␤ Ϫ/Ϫ mice were generated as previously described (7). HTLV-I Tg mice, originally produced by injecting the LTR-env-pX-LTR region of the HTLV-I genome into a (C3H/HeN ϫ C57BL/6J)F 1 ovum (18), were backcrossed to BALB/cA mice (Clea, Tokyo, Japan) for 12 generations and then were used for the experiments.…”

“…Mice with the H-2 q/q haplotype were selected at the second generation by polymerase chain reaction (PCR) using D17MIT 22-specific primers (27). The genotype of each cytokine gene was also examined by PCR using specific primers for each cytokine (7).…”

“…It has been shown that IL-1 can induce many other genes. For example, we have demonstrated that IL-1␤ induces the IL-1␣ gene, and vice versa (7). IL-1 also induces IL-6 and cyclooxygenase 2 genes (8).…”

L’implantation embryonnaire

“…Cependant, ces expériences n'ont jamais pu être reproduites [7,23]. D'autre part, il n'y a pas d'altération majeure de la fertilité chez des souris dont les gènes codant pour les molécules IL1 , l'IL1 , l'IL18 ou IL1R1 ont été invalidés [40,41]. Cependant, nous savons aujourd'hui qu'un gène ne possède pas qu'une seule fonction et que les cytokines membres de la famille de l'IL-1 fonctionnent en réseau.…”