p38 mitogen-activated protein kinase regulates growth factor-induced mitogenesis of rat pulmonary myofibroblasts

Am J Respir Cell Mol Biol. 2002 Dec;27(6):759-65. doi: 10.1165/rcmb.2002-0070OC.

Abstract

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.

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Cell Division / physiology
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology
  • Fibroblasts / cytology*
  • Fibroblasts / enzymology*
  • Growth Substances / pharmacology*
  • Imidazoles / pharmacology
  • Lung / cytology*
  • Male
  • Mitogen-Activated Protein Kinase 1 / analysis
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / analysis
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Platelet-Derived Growth Factor / pharmacology
  • Precipitin Tests
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Enzyme Inhibitors
  • Growth Substances
  • Imidazoles
  • Platelet-Derived Growth Factor
  • Pyridines
  • Epidermal Growth Factor
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580