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Physiology and Pharmacology of Temperature Regulation

Impaired febrile responses to immune challenge in mice deficient in microsomal prostaglandin E synthase-1

¹Centre for Structural Biochemistry, Karolinska Institutet, Huddinge; ²Department of Cell Biology, Faculty of Health Sciences, University of Linköping, Linköping; and ³Departments of Medicine and of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Submitted 29 December 2004 ; accepted in final form 20 January 2005

Fever is a common, centrally elicited sign of inflammatory and infectious processes and is known to be induced by the action of PGE₂ on its specific receptors in the thermogenic region of the hypothalamus. In the present work, using genetically modified mice, we examined the role of the inducible terminal PGE₂-synthesizing enzyme microsomal prostaglandin E synthase-1 (mPGES-1) for the generation of immune-elicited fever. Animals with a deletion of the Ptges gene, which encodes mPGES-1, or their wild-type littermates were given either a subcutaneous injection of turpentine—a model for aseptic cytokine-induced pyresis—or an intraperitoneal injection of interleukin-1. While both procedures resulted in typical febrile responses in wild-type animals, these responses were strongly impaired in the mPGES-1 mutant mice. In contrast, both genotypes showed psychogenic stress-induced hyperthermia and displayed normal diurnal temperature variations. Both wild-type and mPGES-1 mutant mice also showed strongly reduced motor activity following turpentine injection. Taken together with previous observations on mPGES-1 induction in the brain vasculature during various inflammatory conditions and its role in endotoxin-induced pyresis, the present findings indicate that central PGE₂ synthesis by mPGES-1 is a general and critical mechanism for fever during infectious and inflammatory conditions that is distinct from the mechanism(s) underlying the circadian temperature regulation and stress-induced hyperthermia, as well as the inflammation-induced activity depression.

fever; interleukin; prostaglandin

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