The Role of Interleukin-6 in Lipopolysaccharide-Induced Fever by Mechanisms Independent of Prostaglandin E2

Abstract

Fever has been shown to be elicited by prostaglandin E2 (PGE2) binding to its receptors on thermoregulatory neurons in the anterior hypothalamus. The signals that trigger PGE2 production are thought to include proinflammatory cytokines, such as IL-6. However, although the presence of IL-6 is critical for fever, IL-6 by itself is not or only weakly pyrogenic. Here we examined the relationship between IL-6 and PGE2 in lipopolysaccharide (LPS)-induced fever. Immune-challenged IL-6 knockout mice did not produce fever, in contrast to wild-type mice, but the expression of the inducible PGE2-synthesizing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase-1, was similarly up-regulated in the hypothalamus of both genotypes, which also displayed similarly elevated PGE2 levels in the cerebrospinal fluid. Nevertheless, both wild-type and knockout mice displayed a febrile response to graded concentrations of PGE2 injected into the lateral ventricle. There was no major genotype difference in the expression of IL-1β and TNFα or their receptors, and pretreatment of IL-6 knockout mice with soluble TNFα receptor ip or intracerebroventricularly or a cyclooxygenase-2 inhibitor ip did not abolish the LPS unresponsiveness. Hence, although IL-6 knockout mice have both an intact PGE2 synthesis and an intact fever-generating pathway downstream of PGE2, endogenously produced PGE2 is not sufficient to produce fever in the absence of IL-6. The findings suggest that IL-6 controls some factor(s) in the inflammatory cascade, which render(s) IL-6 knockout mice refractory to the pyrogenic action of PGE2, or that it is involved in the mechanisms that govern release of synthesized PGE2 onto its target neurons.