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

Author:

Ning Wen1,Song Ruiping1,Li Chaojun1,Park Edward2,Mohsenin Amir3,Choi Augustine M. K.1,Choi Mary E.4

Affiliation:

1. Pulmonary, Allergy and Critical Care Medicine and

2. Division of Pulmonary Medicine, Johns Hopkins University, Baltimore, Maryland 21205; and

3. Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut 06250

4. Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213;

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-1enhancer/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.

Publisher

American Physiological Society

Subject

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

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