Transforming growth Factor-beta1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway

Am J Respir Crit Care Med. 2001 Jan;163(1):152-7. doi: 10.1164/ajrccm.163.1.2005069.

Abstract

Myofibroblasts play an important role in the fibrogenic process of pulmonary fibrosis. Transforming growth factor (TGF)-beta is well known to induce the phenotypic modulation of fibroblasts to myofibroblasts; however, the intracellular signal regulating induction of the myofibroblastic phenotype of human lung fibroblasts (HLF) has not been determined. In the present study, we examined the role of the mitogen-activated protein kinase (MAPK) superfamily in inducing the phenotypic modulation of HLF to myofibroblasts characterized by alpha-smooth-muscle actin expression, in order to clarify this issue. The results showed that: (1) TGF-beta1 caused the phenotypic modulation of HLF to myofibroblasts in a dose- and a time-dependent manner; (2) TGF-beta1 induced increases in c-Jun-NH2- terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (Erk) phosphorylation and activity; (3) the inhibitors CEP-1347, SB 203580, and PD 98059 attenuated TGF-beta1-induced JNK, p38 MAPK, and Erk activity, respectively; and (4) CEP-1347, but not SB 203580 or PD 98059, attenuated the TGF-beta1-induced phenotypic modulation of HLF to myofibroblasts in a dose-dependent manner. These results indicate that TGF-beta1 is capable of inducing the myofibroblastic phenotype of HLF, and that JNK regulates the phenotypic modulation of TGF-beta1-stimulated HLF to myofibroblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbazoles / pharmacology
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / physiology*
  • Flavonoids / pharmacology
  • Humans
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • JNK Mitogen-Activated Protein Kinases*
  • Lung / immunology
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases / physiology*
  • Mitogen-Activated Protein Kinases / physiology*
  • Muscles / cytology
  • Phenotype
  • Phosphorylation
  • Pyridines / pharmacology
  • Transforming Growth Factor beta / physiology*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Carbazoles
  • Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Indoles
  • Pyridines
  • Transforming Growth Factor beta
  • 3,9-bis((ethylthio)methyl)-K-252a
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • SB 203580
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one