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

Linköping University, Faculty of Health Sciences, Department of Clinical and Experimental Medicine, Division of Cell Biology, SE-581 85 Linköping, Sweden

Address all correspondence and requests for reprints to: Camilla Nilsberth, Linköping University, Faculty of Health Sciences, Department of Clinical and Experimental Medicine, Division of Cell Biology, SE-581 85 Linköping, Sweden. E-mail: camni{at}ibk.liu.se.

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 TNF or their receptors, and pretreatment of IL-6 knockout mice with soluble TNF 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.