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

Abstract

-Fever is a common, centrally elicited sign of inflammatory and infectious processes and is known to be induced by the action of PGE 2 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 PGE 2-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 endotoxininduced pyresis, the present findings indicate that central PGE 2 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 FEVER IS AN ADAPTIVE RESPONSE to infectious and inflammatory processes that is elicited and coordinated by the central nervous system. Fever, traditionally, has been thought to be initiated by pyrogenic cytokines acting on the preoptic area of brain (3,6,45), but because the blood-brain barrier is impermeable to cytokines, the mechanism by which these peripheral signals are transmitted into central nervous signals was long obscure. However, recent studies carried out in this and other laboratories have demonstrated that immune stimuli, such as peripheral administration of cytokines or LPS, as well as chronic inflammatory conditions such as adjuvant-induced arthritis, evoke the expression of the inducible PGE 2 synthesizing enzymes cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) (24) in brain vascular cells (5,8,10,12,26,56), indicating that the peripheral immune signals are transduced in these cells into a prostaglandin signal (1, 2). These observations, which are consistent with findings suggesting a critical role for PGE 2 in the generation of fever (21, 47, 53), were further corroborated in studies of mPGES-1-deficient mice. In contrast to wild-type controls, these mice showed no fever and no central PGE 2 synthesis after peripheral injection of LPS, but they displayed an intact and receptor-specific pyretic capacity in response to centrally administered PGE 2 (14).While these observations demonstrat...

Interleukin-1β induced activation of the hypothalamus–pituitary–adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells

“…intraperitoneally or intravenously via the tail vein. This dose has previously been shown to evoke the centrally elicited acute phase responses fever and anorexia in mice (Elander et al, 2007;Saha et al, 2005). Three hours later, the animals were killed by asphyxiation with CO2 and decapitated.…”

Fever suppression in near-term pregnant rats is dissociated from LPS-activated signaling pathways

“…COX-2 converts arachidonic acid to prostaglandin H 2 (PGH 2 ). Subsequently, a downstream microsomal prostaglandin synthase converts this unstable PGH 2 into PGE 2 (35,61). The resulting PGE 2 binds to its receptors to reduce heat loss and to augment heat retention, thus increasing body temperature (56).…”

La mPGES-1 : elle nous rend malades !

“…La synthèse de PGE2 induite en réponse au LPS dans l'hypothalamus de ces animaux Ptges -/-est fortement atténuée par rapport à celle d'animaux sauvages. En accord avec ces résultats, une autre équipe démontra que les souris invalidées pour la mPGES-1 étaient éga-lement résistantes à la réponse fébrile induite par l'injection d'une cytokine inflammatoire, l'interleukine-1β (IL-1β) [9]. Parallèlement, notre laboratoire a démontré le rôle essentiel de cette enzyme dans l'anorexie observée lors d'une inflammation aiguë induite par une injection d'IL-1β [10].…”

“…CARMA1 change alors de conformation et autorise l'association de BCL10/MALT1 nécessaire à la formation du signalosome [8]. Le CBM participe également à la propagation des lymphomes B de type ABC-DLBCL (activated B cell-like diffuse large B-cell lymphoma), dont la survie repose sur une activité aberrante de NF-κB [9]. Comprendre les modes de régulation du CBM en conditions physiologiques comme pathologiques se révèle donc être un enjeu majeur.…”