Primary Role of Interleukin-1α and Interleukin-1β in Lipopolysaccharide-Induced Hypoglycemia in Mice

Abstract

Within a few hours of its injection into mice, lipopolysaccharide (LPS) induces hypoglycemia and the production of various cytokines. We previously found that interleukin-1α (IL-1α), IL-1β, and tumor necrosis factor alpha (TNF-α) induce hypoglycemia and that the minimum effective dose of IL-1α or IL-1β is about 1/1,000 that of TNF-α. In the present study, we examined the contribution made by IL-1 to the hypoglycemic action of LPS. Nine other cytokines tested were all inactive at inducing hypoglycemia. LPS produced hypoglycemia in mice deficient in either IL-1α or IL-1β but not in mice deficient in both cytokines (IL-1α and -1β knockout [IL-1α/β KO] mice). IL-1α, IL-1β, and TNF-α induced hypoglycemia in IL-1α/β KO mice, as they did in normal control mice. The LPS-induced elevation of serum cortisol was weaker in IL-1α/β KO mice than in control mice, and, in the latter, serum cortisol was markedly raised while blood glucose was declining. IL-1α decreased blood glucose both in NOD mice (which have impaired insulin production) and in KK-Ay mice (insulin resistant). These results suggest that (i) cortisol may not be involved in mediating the resistance of IL-1α/β KO mice to the hypoglycemic action of LPS, (ii) as a mediator, IL-1 is a prerequisite for the hypoglycemic action of LPS, (iii) IL-1α and IL-1β perform mutual compensation, and (iv) IL-1 plays a role as the primary stimulator of the many anabolic reactions required for the elaboration of immune responses against infection.