title: Anti-inflammatory role of microsomal prostaglandin E synthase-1 in a model of neuroinflammation.
abstract: A major immunological response during neuroinflammation is the activation of microglia, which subsequently release proinflammatory mediators such as prostaglandin E(2) (PGE(2)). Besides its proinflammatory properties, cyclooxygenase-2 (COX-2)-derived PGE(2) has been shown to exhibit anti-inflammatory effects on innate immune responses. Here, we investigated the role of microsomal PGE(2) synthase-1 (mPGES-1), which is functionally coupled to COX-2, in immune responses using a model of lipopolysaccharide (LPS)-induced spinal neuroinflammation. Interestingly, we found that activation of E-prostanoid (EP)2 and EP4 receptors, but not EP1, EP3, PGI(2) receptor (IP), thromboxane A(2) receptor (TP), PGD(2) receptor (DP), and PGF(2) receptor (FP), efficiently blocked LPS-induced tumor necrosis factor α (TNFα) synthesis and COX-2 and mPGES-1 induction as well as prostaglandin synthesis in spinal cultures. In vivo, spinal EP2 receptors were up-regulated in microglia in response to intrathecally injected LPS. Accordingly, LPS priming reduced spinal synthesis of TNFα, interleukin 1β (IL-1β), and prostaglandins in response to a second intrathecal LPS injection. Importantly, this reduction was only seen in wild-type but not in mPGES-1-deficient mice. Furthermore, intrathecal application of EP2 and EP4 agonists as well as genetic deletion of EP2 significantly reduced spinal TNFα and IL-1β synthesis in mPGES-1 knock-out mice after LPS priming. These data suggest that initial inflammation prepares the spinal cord for a negative feedback regulation by mPGES-1-derived PGE(2) followed by EP2 activation, which limits the synthesis of inflammatory mediators during chronic inflammation. Thus, our data suggest a role of mPGES-1-derived PGE(2) in resolution of neuroinflammation.
authors.affiliation: Institute of Clinical Pharmacology, Pharmazentrum Frankfurt, ZAFES, Hospital of the Goethe-University, 60590 Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Brenneis
authors.forename: Ovidiu
authors.initials: O
authors.lastname: Coste
authors.forename: Kai
authors.initials: K
authors.lastname: Altenrath
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Claus-Dieter
authors.initials: CD
authors.lastname: Schuh
authors.forename: Dong Dong
authors.initials: DD
authors.lastname: Zhang
authors.forename: Marina
authors.initials: M
authors.lastname: Henke
authors.forename: Andreas
authors.initials: A
authors.lastname: Weigert
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
authors.forename: Barry
authors.initials: B
authors.lastname: Rubin
authors.forename: Rolf
authors.initials: R
authors.lastname: Nusing
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009187:Myelitis / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D011453:Prostaglandins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D011453:Prostaglandins; D044006:Receptors, Epoprostenol; D018078:Receptors, Prostaglandin E; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014409:Tumor Necrosis Factor-alpha; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C489691:Ptgs2 protein, rat; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; C497818:Ptges protein, rat