Oncostatin M enhances the expression of prostaglandin E2 and cyclooxygenase-2 in astrocytes: synergy with interleukin-1beta, tumor necrosis factor-alpha, and bacterial lipopolysaccharide.
Oncostatin M (OSM), a cytokine of the interleukin-6 family, is expressed in rheumatoid arthritis, multiple sclerosis, multiple myeloma, and other inflammatory and neoplastic conditions. Prostaglandin E(2) (PGE(2)), an eicosanoid also associated with inflammation and cancer, has recently been shown to induce OSM expression. We report here that OSM in turn induces PGE(2) production by astrocytes and astroglioma cells. More importantly, in combination with the inflammatory mediators IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide, OSM exhibits a striking synergy, resulting in up to 50-fold higher PGE(2) production by astrocytes, astroglioma, and neuroblastoma cell lines. Enhanced PGE(2) production by OSM and IL-1beta treatment is explained by their effect on cyclooxygenase-2 (COX-2), an enzyme that catalyzes the committed step in PGE(2) synthesis. Of the enzymes involved in PGE(2) biosynthesis, only COX-2 mRNA and protein levels are synergistically amplified by OSM and IL-1beta. Nuclear run-on assays demonstrate that OSM and IL-1beta synergistically upregulate transcription of the COX-2 gene, and the mRNA stability assay indicates that COX-2 mRNA is posttranscriptionally stabilized by OSM and IL-1beta. To effect synergy on the PGE(2) level, OSM signals in part through its gp130/OSMRbeta receptor, since neutralizing antibodies against gp130 and OSMRbeta, but not LIFRbeta, decrease PGE(2) production in response to OSM plus IL-1beta. SB202190 and U0126, inhibitors of p38 MAPK and ERK1/2 activation, respectively, inhibit IL-1beta and OSM upregulation of COX-2 and PGE(2), indicating that these MAPK cascades are utilized by both stimuli. This mechanism of PGE(2) amplification may be active in brain pathologies where both OSM and IL-1beta are present, such as glioblastomas and multiple sclerosis.
Repovic
Pavle
P
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Mi
Kaihong
K
Benveniste
Etty N
EN
D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D001254:Astrocytoma; D001932:Brain Neoplasms; D051546:Cyclooxygenase 2; D050822:Cytokine Receptor gp130; D015232:Dinoprostone / Q000378:metabolism*; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D054513:Group IV Phospholipases A2; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009447:Neuroblastoma; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D010741:Phospholipases A / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018121:Receptors, Cytokine / Q000378:metabolism; D053677:Receptors, Oncostatin M; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D015703:Antigens, CD; D000970:Antineoplastic Agents; C494199:IL6ST protein, human; D007375:Interleukin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508351:OSM protein, human; D010455:Peptides; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D053677:Receptors, Oncostatin M; D014409:Tumor Necrosis Factor-alpha; D053683:Oncostatin M; D050822:Cytokine Receptor gp130; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D015232:Dinoprostone