title: Oncostatin M regulates SOCS3 mRNA stability via the MEK-ERK1/2-pathway independent of p38(MAPK)/MK2.
abstract: The induction of suppressor of cytokine signalling (SOCS)3 expression context dependently involves regulation of SOCS3 transcript stability as previously demonstrated for MAPK activated protein kinase (MK)2-dependent regulation of SOCS3 expression by TNFα (Ehlting et al., 2007). In how far the IL-6-type cytokine OSM, which in contrast to IL-6 is a strong activator of p38(MAPK)/MK2 signalling, also involves regulation of transcript stability and activation of MK2 to induce SOCS3 expression is unclear. In contrast to IL-6, OSM induces SOCS3 expression in murine fibroblasts and in primary human and murine hepatocytes, but not in macrophages because the latter lack the OSM receptor (OSMR)β subunit. Evidence is provided that regulation of OSM-induced expression of SOCS3 involves MEK1- and Erk1/2-mediated stabilization of the SOCS3 transcript. Consistently, OSM-induced stabilization of the SOCS3 transcript is impaired in the presence of inhibitors that specifically block activation of MEK1/2 (U0126) and ERK1/2 (FR180204) or upon knock-down of ERK1/2 expression using specific siRNA. As a potential target site that integrates the stability regulating effect of OSM and OSM-induced activation of MEK1/2 and ERK1/2 a region containing three copies of a pentameric AUUUA motif located within position 2422 and 2541 in closed proximity to the 3' UTR of the SOCS3 transcript has been identified. Unexpectedly, activation of the p38(MAPK)/MK2 pathway, which apart from STAT3 and ERK1/2, is also strongly activated by OSM in human and murine hepatocytes and murine fibroblasts is dispensable for stabilization of the SOCS3 transcript as suggested from inhibitor studies using the p38(MAPK) inhibitor SB203580 or from the analysis of MK2-deficient hepatocytes. However, analysis of MK2-deficient macrophages and hepatocytes revealed that, although MK2 is dispensable for regulation of OSM-induced SOCS3 expression, MK2 is essential for LPS-induced OSM production in macrophages and limits the overall availability of the OSMRβ subunit in hepatocytes. Thus MK2 plays a role for the induction and sensing of OSM-mediated intercellular signalling between macrophages and hepatocytes during LPS-induced inflammation.
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ehlting
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Böhmer
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Maximilian J
authors.initials: MJ
authors.lastname: Hahnel
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, 30623 Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: Department of Surgery (A), Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Wolfram T
authors.initials: WT
authors.lastname: Knoefel
authors.affiliation: Department of Surgery (A), Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Schulte Am Esch
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich Heine University of Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany. Electronic address: Johannes.Bode@med.uni-duesseldorf.de.
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Bode
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053683:Oncostatin M / Q000494:pharmacology*; D053681:Oncostatin M Receptor beta Subunit / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D015850:Interleukin-6; C508348:OSMR protein, human; D053681:Oncostatin M Receptor beta Subunit; D012333:RNA, Messenger; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053683:Oncostatin M; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Extracellular-regulated kinase 1 and 2; Mitogen-activated protein kinase; Oncostatin M; Oncostatin M receptor β; Suppressor of cytokine signalling 3; Transcript stability