TGF-β1 stimulates HO-1 via the p38 mitogen-activated protein kinase in A549 pulmonary epithelial cells

Wen Ning, Ruiping Song, Chaojun Li, Edward Park, Amir Mohsenin, Augustine M.K. Choi, Mary E. Choi

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

In lung injury and progressive lung diseases, the multifunctional cytokine transforming growth factor-β1 (TGF-β1) 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-β1 is a potent inducer of HO-1 and examined the signaling pathway by which TGF-β1 regulates HO-1 expression in human lung epithelial cells (A549). TGF-β1 (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-β1-responsive HO-1 mRNA expression, indicating a requirement for transcription and de novo protein synthesis. Furthermore, TGF-β1 rapidly activated the p38 mitogen-activated protein kinase (p38 MAPK) pathway in A549 cells. A chemical inhibitor of p38 MAPK (SB-203580) abolished TGF-β1-inducible HO-1 mRNA expression. Both SB-203580 and expression of a dominant-negative mutant of p38 MAPK inhibited TGF-β1-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-β1.

Original languageEnglish (US)
Pages (from-to)L1094-L1102
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume283
Issue number5 27-5
DOIs
StatePublished - Nov 1 2002

Keywords

  • Heme oxygenase
  • Inflammation
  • Mitogen-activated protein kinase
  • Oxidant stress
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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