title: Ets-1 regulates TNF-alpha-induced matrix metalloproteinase-9 and tenascin expression in primary bronchial fibroblasts.
abstract: Increased subepithelial deposition of extracellular matrix proteins is a key feature in bronchial asthma. Matrix metalloproteinase-9 (MMP-9) is a proteolytic enzyme that degrades the extracellular matrix. Tenascin is an extracellular matrix glycoprotein that is abundant in thickened asthmatic subbasement membrane. The expression of MMP-9 and tenascin reflects disease activity in asthma and airway remodeling. The molecular mechanisms regulating the expression of these proteins remain unknown. Both MMP-9 and tenascin promoters contain an Ets binding site, suggesting control by Ets-1. Thus, we hypothesized that Ets-1 expression is increased in asthma and that it contributed to enhanced MMP-9 and tenascin expression. To test this hypothesis, we determined the expression of Ets-1 in bronchial biopsies obtained from asthmatic subjects and determined the expression of Ets-1, MMP-9, and tenascin by bronchial fibroblasts activated ex vivo. We observed that nuclear extracts from TNF-alpha-activated fibroblasts showed increased Ets-binding activity. In addition, TNF-alpha-activated fibroblasts had increased expression of Ets-1 mRNA and protein, which preceded an increase in MMP-9 and tenascin mRNA. Furthermore, treatment of fibroblasts with Ets-1 antisense oligonucleotides down-regulated TNF-alpha-induced Ets-1, MMP-9, and, to a lesser extent, tenascin protein expression or activity. Taken together, these data demonstrate that TNF-alpha increases MMP-9 and tenascin expression in bronchial fibroblasts via the transcription factor Ets-1, and suggest a role for Ets-1 in airway remodeling in asthma.
authors.affiliation: Department of Medicine-Pulmonary and Critical Care Section, University of Wisconsin, Madison, WI 53792, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Stéphane
authors.initials: S
authors.lastname: Esnault
authors.forename: Takashi
authors.initials: T
authors.lastname: Maeda
authors.forename: Elizabeth A B
authors.initials: EA
authors.lastname: Kelly
authors.forename: James S
authors.initials: JS
authors.lastname: Malter
authors.forename: Nizar N
authors.initials: NN
authors.lastname: Jarjour
mesh_terms: D000328:Adult; D001249:Asthma / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004790:Enzyme Induction / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000378:metabolism; D019063:Tenascin / Q000096:biosynthesis* / Q000235:genetics; D013873:Thionucleotides / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C494041:ETS1 protein, human; D016376:Oligonucleotides, Antisense; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D019063:Tenascin; D013873:Thionucleotides; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9; D016650:Fluorescein-5-isothiocyanate