Impaired febrile responses to immune challenge in mice deficient in microsomal prostaglandin E synthase-1.
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-1beta. 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.
Saha
Sipra
S
Centre for Structural Biochemistry, Karolinska Institutet, Huddinge, Sweden.
Engström
Linda
L
Mackerlova
Ludmila
L
Jakobsson
Per-Johan
PJ
Blomqvist
Anders
A
D000818:Animals; D002940:Circadian Rhythm / Q000502:physiology; D005334:Fever / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology; D007375:Interleukin-1; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology*; D009043:Motor Activity / Q000502:physiology; D000071876:Prostaglandin-E Synthases; D013312:Stress, Physiological; D014425:Turpentine
D007375:Interleukin-1; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D014425:Turpentine