Primary role of interleukin-1α and interleukin-lβ in lipopolysaccharide-induced hypoglycemia in mice

Within a few hours of its injection into mice, lipopolysaccharide (LPS) induces hypoglycemia and the production of various cytokines. We previously found that interleukin-1alpha (IL-1alpha), IL-1beta, and tumor necrosis factor alpha (TNF-alpha) induce hypoglycemia and that the minimum effective dose of IL-1alpha or IL-1beta is about 1/1,000 that of TNF-alpha. 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-1alpha or IL-1beta but not in mice deficient in both cytokines (IL-1alpha and -1beta knockout [IL-1alpha/beta KO] mice). IL-1alpha, IL-1beta, and TNF-alpha induced hypoglycemia in IL-1alpha/beta KO mice, as they did in normal control mice. The LPS-induced elevation of serum cortisol was weaker in IL-1alpha/beta KO mice than in control mice, and, in the latter, serum cortisol was markedly raised while blood glucose was declining. IL-1alpha 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-1alpha/beta 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-1alpha and IL-1beta 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.