Transforming Growth Factor- β₁ Induces Phenotypic Modulation of Human Lung Fibroblasts to Myofibroblast Through a c-Jun-NH₂-Terminal Kinase-Dependent Pathway

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.

Nicotine inhibits myofibroblast differentiation in human gingival fibroblasts

“…A study using lung fibroblasts found that TGF-β1 up-regulated c-Jun NH 2 -terminal kinase (JNK), p38 MAPK, and extracellular regulated kinase (ERK) phosphorylation and activity. However, only CEP-1347 (a specific inhibitor of the JNK-mediated signaling pathway), but not SB 203580 or PD 98059 (inhibitors of p38 MAPK and ERK kinase respectively) decreased the TGF-β1-induced myofibroblast differentiation in a dose dependent manner [Hashimoto et al, 2001]. These data suggested that TGF-β1-activated JNK pathway regulated myofibroblast differentiation.…”

FAK Is Required for TGFβ-induced JNK Phosphorylation in Fibroblasts: Implications for Acquisition of a Matrix-remodeling Phenotype

“…Fibroblasts deficient in JNK make excess TGF␤ (Ventura et al, 2004), and overexpression of the JNK target c-jun blocks induction of a generic Smad3-dependent reporter (Verrecchia et al, 2001;Leask et al, 2003). Conversely, TGF␤ induces ␣-SMA in a JNK-dependent manner (Hashimoto et al, 2001) and c-jun augments TGF␤-induction of 12-O-tetradecanoyl-13-acetate (TPA)-responsive gene promoter (TRE) elements that contain AP-1 sites (Zhang et al, 1998).…”

Role of tissue stroma in cancer cell invasion

“…Smad7 prevents the phosphorylation of Smad2 or Smad3 and, consequently, nuclear translocation. CEP-1347, an inhibitor of JNK-mediated signalling and currently in clinical trial for Alzheimer's and Parkinson's disease, inhibits TGF-β-induced α-SMA expression in fibroblasts [235]. Halofuginone, an antifibrotic agent, h Human origin (unless mentioned otherwise); § fibroblasts were pretreated with TGF-β.…”