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Articles in PresS, published online ahead of print August 2, 2002
Am J Physiol Lung Cell Mol Physiol, 10.1152/ajplung.00151.2002
Submitted on May 15, 2002
Accepted on July 16, 2002
1 Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2 Division of Pulmonary Medicine, Johns Hopkins University, Baltimore, MD, USA
3 Section of Nephrology, Yale University School of Medicine, New Haven, CT, USA
* To whom correspondence should be addressed. E-mail: choiam{at}msx.upmc.edu.
In lung injury and progressive lung diseases, the multifunctional cytokine transforming growth factor-ß1 (TGF-ß1) 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-ß1 is a potent inducer of HO-1 and examined the signaling pathway by which TGF-ß1 regulates HO-1 expression in human lung epithelial cells (A549). TGF-ß1 (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-ß1-responsive HO-1 mRNA expression, indicating a requirement for transcription and de novo protein synthesis. Furthermore, TGF-ß1 rapidly activated the p38 mitogen activated protein kinase (p38 MAPK) pathway in A549 cells. A chemical inhibitor of p38 MAPK (SB203580) abolished TGF-ß1-inducible HO-1 mRNA expression. Both SB203580 and expression of a dominant-negative mutant of p38 MAPK inhibited TGF-ß1-induced ho-1 gene activation, as assayed by luciferase activity of a 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-ß1.
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