Transforming growth factor-beta(1) 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 pulmonar y fibrosis. Transforming growth factor (TCF)-beta is well known to induce t he phenotypic modulation of fibroblasts to myofibroblasts; however, the int racellular 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) superf amily in inducing the phenotypic modulation of HLF to myofibroblasts charac terized by a-smooth-muscle actin expression, in order to clarify this issue . The results showed that: (1) TGF-beta (1) caused the phenotypic modulatio n 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, an d 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, bu t not SE 203580 or PD 98059, attenuated the TGF-beta (1)-induced phenotypic modulation of HLF to myofibroblasts in a dose-dependent manner. These resu lts indicate that TCF-beta (1) is capable of inducing the myofibroblastic p henotype of HLF, and that JNK regulates the phenotypic modulation of TGF-be ta (1)-stimulated HLF to myofibroblasts.