Involvement of central microsomal prostaglandin E synthase-1 in IL-1β-induced anorexia

Pecchi, Émilie; Dallaporta, Michel; Thirion, Sylvie; Salvat, Colette; Bérenbaum, Francis; Jean, André; Troadec, Jean‐Denis

doi:10.1152/physiolgenomics.00306.2005

Cited by 47 publications

(37 citation statements)

References 29 publications

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“…Sickness-induced anorexia has also been shown to be mediated by PGE2 (Pecchi et al, 2006), although not exclusively. While being reversed by COX-2 inhibitors (Johnson et al, 2002;Lugarini et al, 2002), the anorectic response driven by inflammation-induced PGE2 is dependent on the type of immune stimuli.…”

Section: Anorexiamentioning

confidence: 99%

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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The immune-to-brain signaling is a critical survival factor when the body is confronted by pathogens, and in particular by microorganisms. During infections, the ability of the immune system to engage the central nervous system (CNS) in the management of the inflammatory response is just as important as its ability to mount a specific immune response against the pathogen, since the CNS can provide a systemic negative feed-back to the immune activation by release of stress hormones and also can prioritize the usage of the energy resources by the vital organs. Prostaglandin E2 (PGE2) and pro-inflammatory cytokines were among the first mediators to be identified to participate in the immune-to-brain signaling, a process that is clinically recognized by the development of manifestations of common illness such as fever, anorexia, decreased social interactions, lethargy, sleepiness, and hyperalgesia.In this thesis the contribution of PGE2 to the immune-to-brain signaling was further characterized at the blood-brain-barrier (BBB) and in the anterior preoptic area (POA) of the hypothalamus (i.e. the thermoregulatory region or, in sickness, the fever generating region).BBB is the major interface region between peripheral circulating cytokines and the neuronal parenchyma and a critical source of PGE2. Using chimeric mice lacking the inducible enzyme for PGE2 synthesis, microsomal PGE synthase-1 (mPGES-1), in either hematopoietic or nonhematopoietic cells, we demonstrate in paper I that brain endothelial cells are the critical source of PGE2 in BBB during peripheral inflammation. For the demonstration of the mPGES-1 expression in the BBB cells we developed in paper I a method for enzymatic dissociation of these cells, followed by fluorescence activated cell sorting (FACS). Using the same method, we show in paper II that the BBB response to immune stimuli is towards an increased production of PGE2 in endothelial cells and an increased sensitivity of these cells for proinflammatory cytokines. These changes are supported by decreased PGE2 degradation and decreased synthesis of other prostanoids in perivascular macrophages, which hence respond in concordance with the endothelial cells in enhancing PGE2 signaling.Once released in the neuronal tissue, PGE2 has been shown to be critical for the fever response by acting on the type 3 PGE2 receptors (EP3) within POA. By laser capture microdissection (LCM) we extracted the EP3 receptor expressing region in POA, defined by in situ hybridization histochemistry, from mouse brain sections. We demonstrate in paper III that the predominant subtypes of the EP3 receptor in POA are EP3α and EP3γ. In paper IV we further analyze the effect of PGE2 on the LCM dissected EP-rich POA using gene expression microarrays. We demonstrate that PGE2 has a limited effect on the gene expression changes within POA, suggesting that the neuronal activity is modulated by PGE2 in a transcriptionindependent manner and that the profound gene expression changes that are seen in the CNS during inflammation ...

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Section: Anorexiamentioning

confidence: 99%

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

Vasilache¹

2015

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“…Metabolic syndrome accompanies chronic, low-grade inflammation in the hypothalamic arcuate nucleus, and PGE 2 decreases feeding behaviors via its receptor, EP3 [67]. iL-1β induces anorexia in normal mice, whereas it fails to decrease food intake in Ptges -/-mice [64]. Thus, the central mPGES-1/EP3 axis is involved in feeding control and is essential for immune anorexic behavior, and thus may constitute a potential therapeutic target.…”

Section: Cancermentioning

confidence: 99%

Lipid Mediators in Life Science

Murakami

2011

Exp. Anim.

128

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"Lipid mediators" represent a class of bioactive lipids that are produced locally through specific biosynthetic pathways in response to extracellular stimuli. They are exported extracellularly, bind to their cognate G protein-coupled receptors (GPCRs) to transmit signals to target cells, and are then sequestered rapidly through specific enzymatic or non-enzymatic processes. Because of these properties, lipid mediators can be regarded as local hormones or autacoids. Unlike proteins, whose information can be readily obtained from the genome, we cannot directly read out the information of lipids from the genome since they are not genome-encoded. However, we can indirectly follow up the dynamics and functions of lipid mediators by manipulating the genes encoding a particular set of proteins that are essential for their biosynthesis (enzymes), transport (transporters), and signal transduction (receptors). Lipid mediators are involved in many physiological processes, and their dysregulations have been often linked to various diseases such as inflammation, infertility, atherosclerosis, ischemia, metabolic syndrome, and cancer. In this article, I will give an overview of the basic knowledge of various lipid mediators, and then provide an example of how research using mice, gene-manipulated for a lipid mediator-biosynthetic enzyme, contributes to life science and clinical applications.

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“…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]. De plus, nous avons également pu montrer l'implication de la mPGES-1 dans le syndrome anorexie/cachexie (inflammation chronique) qui se développe en réponse à l'implantation sous-cutanée d'une tumeur sécrétrice de cytokines [11].…”

Section: Magazineunclassified

“…De plus, nous avons également pu montrer l'implication de la mPGES-1 dans le syndrome anorexie/cachexie (inflammation chronique) qui se développe en réponse à l'implantation sous-cutanée d'une tumeur sécrétrice de cytokines [11]. Dans ces deux modèles, l'invalidation de la mPGES-1 abolit la réponse anorexique des animaux et limite ainsi leur perte de poids [10,11]. Il est important de noter que cet effet sur l'appétit intervient alors que l'expression centrale de COX-2 est augmentée chez ces animaux et que l'expression constitutive des enzymes mPGES-2 et cPGES n'est pas modifiée [10,11].…”

Section: Magazineunclassified

“…Dans ces deux modèles, l'invalidation de la mPGES-1 abolit la réponse anorexique des animaux et limite ainsi leur perte de poids [10,11]. Il est important de noter que cet effet sur l'appétit intervient alors que l'expression centrale de COX-2 est augmentée chez ces animaux et que l'expression constitutive des enzymes mPGES-2 et cPGES n'est pas modifiée [10,11]. En accord avec ces résultats comportementaux, l'activation des structures cérébrales responsables du maintien de la température corporelle et de l'homéostasie énergétique en réponse à une inflammation périphérique est très diminuée chez les souris invalidées pour la mPGES-1 [12].…”

Section: Magazineunclassified

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