This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rice, A. B. Articles by Bonner, J. C. Search for Related Content PubMed PubMed Citation Articles by Rice, A. B. Articles by Bonner, J. C.

p38 Mitogen-Activated Protein Kinase Regulates Growth Factor–Induced Mitogenesis of Rat Pulmonary Myofibroblasts

Airway Inflammation Group, Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina

Address correspondence to: James C. Bonner, Ph.D., NIEHS, PO Box 12233, Research Triangle Park, NC 27709. E-mail: bonnerj{at}niehs.nih.gov

Myofibroblast proliferation is a central feature of pulmonary fibrogenesis. Several growth factors, including platelet-derived growth factor (PDGF) and epidermal growth factor (EGF), stimulate myofibroblast growth by activating extracellular signal regulated kinases 1 and 2 (ERK1/2). In this report, we demonstrate that PDGF-BB and EGF also activate the p38 mitogen-activated protein (MAP) kinase. Inhibition of p38 activity with the pyridinylimidazole compound SB203580 enhanced both PDGF-BB and EGF-stimulated DNA synthesis in rat lung myofibroblasts. ERK1/2 phosphorylation in response to either PDGF-BB or EGF treatment was significantly increased by pretreatment of cells with SB203580. We also demonstrated that ERK1/2-induced phosphorylation of PHAS-1 substrate was enhanced by inhibition of p38 MAP kinase with SB203580. However, SB203580 did not significantly increase growth factor–induced activation of MEK, the upstream kinase that phosphorylates ERK1/2. p38 MAP kinase was co-immunoprecipitated with ERK-1/2 following growth factor stimulation. Collectively, these data demonstrate that p38 MAP kinase activation negatively regulates PDGF- and EGF-mediated growth responses by directly interacting with ERK1/2 and suppressing its phosphorylation.

Abbreviations: Dulbecco's modified Eagle's medium, DMEM • epidermal growth factor, EGF • extracellular signal-regulated kinases 1 and 2, ERK1/2 • fetal bovine serum, FBS • interleukin, IL • jun amino-terminal kinase, JNK • mitogen-activated protein, MAP • MAP kinase kinase, MEK • phosphate-buffered saline, PBS • platelet-derived growth factor, PDGF • phosphorylated heat- and acid stable protein, PHAS • sodium dodecyl sulfate, SDS • serum-free defined medium, SFDM • tumor necrosis factor, TNF

This article has been cited by other articles:

				J. Ahamed, F. Niessen, T. Kurokawa, Y. K. Lee, G. Bhattacharjee, J. H. Morrissey, and W. Ruf Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia Blood, June 15, 2007; 109(12): 5251 - 5259. [Abstract] [Full Text] [PDF]

				G. Karakiulakis, E. Papakonstantinou, A. J. Aletras, M. Tamm, and M. Roth Cell Type-specific Effect of Hypoxia and Platelet-derived Growth Factor-BB on Extracellular Matrix Turnover and Its Consequences for Lung Remodeling J. Biol. Chem., January 12, 2007; 282(2): 908 - 915. [Abstract] [Full Text] [PDF]

				Z. Wang, H. Yang, S. D. Tachado, J. E. Capo-Aponte, V. N. Bildin, H. Koziel, and P. S. Reinach Phosphatase-Mediated Crosstalk Control of ERK and p38 MAPK Signaling in Corneal Epithelial Cells Invest. Ophthalmol. Vis. Sci., December 1, 2006; 47(12): 5267 - 5275. [Abstract] [Full Text] [PDF]

				V. S. Rajkumar, X. Shiwen, M. Bostrom, P. Leoni, J. Muddle, M. Ivarsson, B. Gerdin, C. P. Denton, G. Bou-Gharios, C. M. Black, et al. Platelet-Derived Growth Factor-{beta} Receptor Activation Is Essential for Fibroblast and Pericyte Recruitment during Cutaneous Wound Healing Am. J. Pathol., December 1, 2006; 169(6): 2254 - 2265. [Abstract] [Full Text] [PDF]

				D. M. Walters, A. Antao-Menezes, J. L. Ingram, A. B. Rice, A. Nyska, Y. Tani, S. R. Kleeberger, and J. C. Bonner Susceptibility of Signal Transducer and Activator of Transcription-1-Deficient Mice to Pulmonary Fibrogenesis Am. J. Pathol., November 1, 2005; 167(5): 1221 - 1229. [Abstract] [Full Text] [PDF]

				H. P. Kim, X. Wang, A. Nakao, S. I. Kim, N. Murase, M. E. Choi, S. W. Ryter, and A. M. K. Choi Caveolin-1 expression by means of p38{beta} mitogen-activated protein kinase mediates the antiproliferative effect of carbon monoxide PNAS, August 9, 2005; 102(32): 11319 - 11324. [Abstract] [Full Text] [PDF]

				T. Gray, P. Nettesheim, C. Loftin, J.-S. Koo, J. Bonner, S. Peddada, and R. Langenbach Interleukin-1{beta}-Induced Mucin Production in Human Airway Epithelium Is Mediated by Cyclooxygenase-2, Prostaglandin E2 Receptors, and Cyclic AMP-Protein Kinase A Signaling Mol. Pharmacol., August 1, 2004; 66(2): 337 - 346. [Abstract] [Full Text] [PDF]