Ets-1 Regulates TNF-α-Induced Matrix Metalloproteinase-9 and Tenascin Expression in Primary Bronchial Fibroblasts

Yutaka Nakamura, Stéphane Esnault, Takashi Maeda, Elizabeth A B Kelly, James S. Malter, Nizar N. Jarjour

Research output: Contribution to journalArticle

53 Scopus citations

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-α-activated fibroblasts showed increased Ets-binding activity. In addition, TNF-α-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-α-induced Ets-1, MMP-9, and, to a lesser extent, tenascin protein expression or activity. Taken together, these data demonstrate that TNF-α 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.

Original languageEnglish (US)
Pages (from-to)1945-1952
Number of pages8
JournalJournal of Immunology
Volume172
Issue number3
StatePublished - Feb 1 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Nakamura, Y., Esnault, S., Maeda, T., Kelly, E. A. B., Malter, J. S., & Jarjour, N. N. (2004). Ets-1 Regulates TNF-α-Induced Matrix Metalloproteinase-9 and Tenascin Expression in Primary Bronchial Fibroblasts. Journal of Immunology, 172(3), 1945-1952.