Transforming growth Factor-beta1 induces phenotypic modulation of human lung fibroblasts to myofibroblast through a c-Jun-NH2-terminal kinase-dependent pathway.
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.
Hashimoto
S
S
First Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
Gon
Y
Y
Takeshita
I
I
Matsumoto
K
K
Maruoka
S
S
Horie
T
T
D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008168:Lung / Q000276:immunology; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009132:Muscles / Q000166:cytology; D010641:Phenotype; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D002227:Carbazoles; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007211:Indoles; D011725:Pyridines; D016212:Transforming Growth Factor beta; C106592:3,9-bis((ethylthio)methyl)-K-252a; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one