Role of Extracellular Signal-Regulated Kinase, p38 Kinase, and Activator Protein-1 in Transforming Growth Factor-β1–Induced Alpha Smooth Muscle Actin Expression in Human Fetal Lung Fibroblasts In Vitro

Abstract

Myofibroblasts characterized by alpha smooth muscle actin(alpha-SMA) expression play a key role in pulmonary fibrosis. Transforming growth factor-beta1 (TGF-beta1) is likely to be involved in the emergence of myofibroblasts, but the intracellular signal pathways for this process have not been well determined. The aim of the present study was to investigate the role of mitogen-activated protein kinase (MAPK)/activator protein-1 (AP-1) signaling pathways in TGF-beta1-induced alpha-SMA expression in human fetal lung fibroblasts (HLF-02). We found that TGF-beta1 treatment activated p38 kinase and extracellular signal-regulated kinase (Erk) in HLF-02 cells. The induction of alpha-SMA by TGF-beta1 was suppressed by p38 kinase inhibitor (SB203580) and Erk inhibitor (PD98059). AP-1 inhibitor curcumin also inhibited TGF-beta1-induced alpha-SMA expression. In addition, dominant negative mutant c-Jun (TAM67) downregulated TGF-beta1-induced AP-1 transactivation and alpha-SMA expression. In additional, PD98059 but not SB203580 inhibited the AP-1 DNA binding activity induced by TGF-beta1. Based on these findings, we conclude that p38 kinase, Erk, and AP-1 are responsible for the alpha-SMA expression induced by TGF-beta1 in human fetal lung fibroblasts. Erk is involved in inducing alpha-SMA expression via AP-1 activation.

Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cells for Inhibiting Myofibroblastic Differentiation of Irradiated Human Lung Fibroblasts

“…The accompanying secretion of cytokines can alter the extracellular matrix, cause inflammation, enhance tissue remodeling and promote fibrosis. Consistent with previous observations, the present study found that irradiated nHLFs showed increased expression of α-SMA, a marker of myofibroblasts that have an important role in lung fibrosis (Hu et al 2006).…”

“…2). Since the fibrosis that occurs in RILI is associated with increased proliferation of nHLFs (Rodemann and Bamberg 1995;Martin et al 2000;Hu et al 2006), we selected 5 Gy as the radiation dose for all subsequent experiments performed in this study.…”

“…Radiation can stimulate lung fibroblasts to secrete cytokines, undergo hyperplasia, and differentiate into myofibroblasts (Martin et al 1993(Martin et al , 2000Rodemann and Bamberg 1995). Myofibroblasts, which show up-regulated expression of α-smooth muscle actin (α-SMA), promote the synthesis of additional collagens; this leads to excessive deposition and abnormal remodeling of the extracellular matrix, a hallmark of RILI (Rodemann and Bamberg 1995;Martin et al 2000;Hu et al 2006).…”

Inhibition of α-SMA by the Ectodomain of FGFR2c Attenuates Lung Fibrosis

“…The genes of α-SMA, PAI-1, TIMP3 and FN1 participate in the deposition of ECM during the process of fibrosis (29)(30)(31). In primary mouse lung fibroblasts, the expression of these genes was upregulated strongly by both TGF-β and FGF-2 but was markedly impaired to varying degrees by sFGFR2c (Figure 4).…”

Impact and significance of EGCG on Smad, ERK, and β-catenin pathways in transdifferentiation of renal tubular epithelial cells

“…TGF-b1-induced fibrosis regulation was achieved by acetylation of Smad3 (Kim et al, 2013b). In vitro experiments have demonstrated that ERK is involved in extracellular matrix formation induced by TGF-b1 (Mucsi et al, 1996;Ramirez et al, 2006;Hu et al, 2006). The TGF-b1-activated kinase, which activates the MAPK pathway, links the TGF-b1 signaling pathway with the MAPK cascade pathway.…”