title: TGF-beta1 stimulates HO-1 via the p38 mitogen-activated protein kinase in A549 pulmonary epithelial cells.
abstract: In lung injury and progressive lung diseases, the multifunctional cytokine transforming growth factor-beta1 (TGF-beta1) modulates inflammatory responses and wound repair. Heme oxygenase-1 (HO-1) is a stress-inducible protein that has been demonstrated to confer cytoprotection against oxidative injury and provide a vital function in maintaining tissue homeostasis. Here we report that TGF-beta1 is a potent inducer of HO-1 and examined the signaling pathway by which TGF-beta1 regulates HO-1 expression in human lung epithelial cells (A549). TGF-beta1 (1-5 ng/ml) treatment resulted in a marked time-dependent induction of HO-1 mRNA in A549 cells, followed by corresponding increases in HO-1 protein and HO enzymatic activity. Actinomycin D and cycloheximide inhibited TGF-beta1-responsive HO-1 mRNA expression, indicating a requirement for transcription and de novo protein synthesis. Furthermore, TGF-beta1 rapidly activated the p38 mitogen-activated protein kinase (p38 MAPK) pathway in A549 cells. A chemical inhibitor of p38 MAPK (SB-203580) abolished TGF-beta1-inducible HO-1 mRNA expression. Both SB-203580 and expression of a dominant-negative mutant of p38 MAPK inhibited TGF-beta1-induced ho-1 gene activation, as assayed by luciferase activity of an ho-1 enhancer/luciferase fusion construct (pMHO1luc-33+SX2). These studies demonstrate the critical intermediacy of the p38 MAPK pathway in the regulation of HO-1 expression by TGF-beta1.
authors.affiliation: Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Ning
authors.forename: Ruiping
authors.initials: R
authors.lastname: Song
authors.forename: Chaojun
authors.initials: C
authors.lastname: Li
authors.forename: Edward
authors.initials: E
authors.lastname: Park
authors.forename: Amir
authors.initials: A
authors.lastname: Mohsenin
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.forename: Mary E
authors.initials: ME
authors.lastname: Choi
mesh_terms: D002460:Cell Line; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics*; D051547:Heme Oxygenase-1; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D008168:Lung; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D008565:Membrane Proteins; D011725:Pyridines; D012333:RNA, Messenger; D011994:Recombinant Proteins; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580