Transforming growth factor-β1 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 (TCF)-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 a-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, SE 203580, and PD 98059 attenuated TGF-beta1-induced JNK, p38 MAPK, and Erk activity, respectively; and (4) CEP-1347, but not SE 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 TCF-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.