title: MSK1 and MSK2 inhibit lipopolysaccharide-induced prostaglandin production via an interleukin-10 feedback loop.
abstract: Prostaglandin production is catalyzed by cyclooxygenase 2 (cox-2). We demonstrate here that MSK1 and MSK2 (MSK1/2) can exert control on the induction of cox-2 mRNA by Toll-like receptor (TLR) agonists. In the initial phase of cox-2 induction, MSK1/2 knockout macrophages confirmed a role for MSK in the positive regulation of transcription. However, at later time points both lipopolysaccharide (LPS)-induced prostaglandin and cox-2 protein levels were increased in MSK1/2 knockout. Further analysis found that while MSKs promoted cox-2 mRNA transcription, following longer LPS stimulation MSKs also promoted degradation of cox-2 mRNA. This was found to be the result of an interleukin 10 (IL-10) feedback mechanism, with endogenously produced IL-10 promoting cox-2 degradation. The ability of IL-10 to do this was dependent on the mRNA binding protein TTP through a p38/MK2-mediated mechanism. As MSKs regulate IL-10 production in response to LPS, MSK1/2 knockout results in reduced IL-10 secretion and therefore reduced feedback from IL-10 on cox-2 mRNA stability. Following LPS stimulation, this increased mRNA stability correlated to an elevated induction of both of cox-2 protein and prostaglandin secretion in MSK1/2 knockout macrophages relative to that in wild-type cells. This was not restricted to isolated macrophages, as a similar effect of MSK1/2 knockout was seen on plasma prostaglandin E2 (PGE2) levels following intraperitoneal injection of LPS.
authors: MRC Protein Phosphorylation Unit, Sir James Black Complex, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors: Kirsty F
authors: KF
authors: MacKenzie
authors: Mirjam W M
authors: MW
authors: Van Den Bosch
authors: Shaista
authors: S
authors: Naqvi
authors: Suzanne E
authors: SE
authors: Elcombe
authors: Victoria A
authors: VA
authors: McGuire
authors: Alastair D
authors: AD
authors: Reith
authors: Perry J
authors: PJ
authors: Blackshear
authors: Jonathan L E
authors: JL
authors: Dean
authors: J Simon C
authors: JS
authors: Arthur
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D011453:Prostaglandins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D059748:Proteolysis; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051546:Cyclooxygenase 2; D016753:Interleukin-10; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D011453:Prostaglandins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C541099:TTP protein, mouse; C077623:Ptgs2 protein, mouse; C485459:Rps6ka4 protein, mouse; C116919:mitogen and stress-activated protein kinase 1
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