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Am. J. Respir. Crit. Care Med., Volume 163, Number 1, January 2001, 152-157

Transforming Growth Factor-beta 1 Induces Phenotypic Modulation of Human Lung Fibroblasts to Myofibroblast Through a c-Jun-NH2-Terminal Kinase-Dependent Pathway

SHU HASHIMOTO, YASUHIRO GON, IKUKO TAKESHITA, KEN MATSUMOTO, SHUICHIRO MARUOKA, and TAKASHI HORIE

First Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan

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-beta 1 caused the phenotypic modulation of HLF to myofibroblasts in a dose- and a time-dependent manner; (2) TGF-beta 1 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-beta 1-induced JNK, p38 MAPK, and Erk activity, respectively; and (4) CEP-1347, but not SB 203580 or PD 98059, attenuated the TGF-beta 1-induced phenotypic modulation of HLF to myofibroblasts in a dose-dependent manner. These results indicate that TGF-beta 1 is capable of inducing the myofibroblastic phenotype of HLF, and that JNK regulates the phenotypic modulation of TGF-beta 1-stimulated HLF to myofibroblasts.




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