title: Oncostatin M causes VEGF release from human airway smooth muscle: synergy with IL-1beta.
abstract: Vascular endothelial growth factor (VEGF), a potent angiogenesis factor, likely contributes to airway remodeling in asthma. We sought to examine the effects and mechanism of action of IL-6 family cytokines on VEGF release from human airway smooth muscle (HASM) cells. Oncostatin M (OSM), but not other IL-6 family cytokines, increased VEGF release, and IL-1beta enhanced OSM-induced VEGF release. OSM increased VEGF mRNA expression and VEGF promoter activity, whereas IL-1beta had no effect. IL-1beta did not augment the effects of OSM on VEGF promoter activity but did augment OSM-induced VEGF mRNA expression and mRNA stability. The STAT3 inhibitor piceatannol decreased both OSM-induced VEGF release and synergy between OSM and IL-1beta, without affecting responses to IL-1beta alone. Piceatannol also inhibited OSM-induced VEGF mRNA expression. In contrast, inhibitors of MAPK pathway had no effect on OSM or OSM plus IL-1beta-induced VEGF release. OSM increased type 1 IL-1 receptor (IL-1R1) mRNA expression, as measured by real-time PCR, and piceatannol attenuated this response. Consistent with the increase in IL-1R1 expression, OSM markedly augmented IL-1beta-induced VEGF, MCP-1, and IL-6 release. In summary, our data indicate OSM causes VEGF expression in HASM cells by a transcriptional mechanism involving STAT3. IL-1beta also synergizes with OSM to increase VEGF release, likely as a result of effects of IL-1beta on VEGF mRNA stability as well as effects of OSM on IL-1R1 expression. This is the first description of a role for OSM on IL-1R1 expression in any cell type. OSM may contribute to airway remodeling observed in chronic airway disease.
authors.affiliation: Physiology Program, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA.
authors.forename: Débora S
authors.initials: DS
authors.lastname: Faffe
authors.forename: Lesley
authors.initials: L
authors.lastname: Flynt
authors.forename: Matthew
authors.initials: M
authors.lastname: Mellema
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Whitehead
authors.forename: Kerri
authors.initials: K
authors.lastname: Bourgeois
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: Eric S
authors.initials: ES
authors.lastname: Silverman
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Shore
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D018836:Inflammation Mediators / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D018836:Inflammation Mediators; D007375:Interleukin-1; D015850:Interleukin-6; C508351:OSM protein, human; D010455:Peptides; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013267:Stilbenes; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D053683:Oncostatin M; C041525:3,3',4,5'-tetrahydroxystilbene; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases