Anti-inflammatory effects of prostaglandin E2 in the central nervous system in response to brain injury and circulating lipopolysaccharide.
Prostaglandin E2, a product of the cyclooxygenation of arachidonic acid released from membrane phospholipids, plays major roles in regulating brain injury and inflammation. Although prostaglandin E2 has frequently been considered as a possible inducer of brain damage and degeneration, it may exert beneficial effects in the CNS. Indeed, in spite of its classic role as a pro-inflammatory molecule, several recent in vitro observations indicate that prostaglandin E2 can inhibit microglial activation. This study investigated the effect of central prostaglandin E2 injection on circulating lipopolysaccharide-induced gene expression of different pro-inflammatory molecules in both vascular and parenchymal elements of the brain. Localized, but strong, expression of tumor necrosis factor-alpha and interleukin-1ss mRNA was found at the edge of the intracerebroventricular tract, which was largely prevented by the central prostaglandin E2 injection. Systemic lipopolysaccharide injection caused a profound transcriptional activation of cyclooxygenase-2 and the inhibitory factor kappaBalpha (IkappaBalpha, index of NF-kappaB activity) in the cerebral endothelium and tumor necrosis factor-alpha in microglial cells across the brain parenchyma. Although exogenous prostaglandin E2 increased lipopolysaccharide-induced NF-kappaB activity and cyclooxygenase-2 transcription in vascular-associated elements, it significantly reduced microglial activation and tumor necrosis factor-alpha expression in the brain parenchyma. These results indicate that prostaglandin E2 may play an important role in modulating the immune response occurring at the injured site and the pro-inflammatory signaling events taking place in both vascular- and microglial-associated elements of the CNS.
Zhang
J
J
Laboratory of Molecular Endocrinology, CHUL Research Center and Department of Anatomy and Physiology, Laval University, Québec, Canada.
Rivest
S
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000473:pathology*; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics; D015232:Dinoprostone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D007276:Injections, Intraventricular; D007527:Isoenzymes / Q000235:genetics; D008070:Lipopolysaccharides / Q000097:blood* / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone