Enhanced
transforming growth factor (
TGF) -beta signaling contributes to
idiopathic pulmonary fibrosis (IPF), a progressive and fatal disease characterized by alveolar epithelial type II (ATII) cell
hyperplasia, (myo)fibroblast accumulation, and excessive extracellular matrix deposition.
TGF-beta is a potent inducer of lung
fibrosis, and it regulates the ATII cell phenotype; however, direct
TGF-beta target genes controlling the ATII cell phenotype remain elusive. Here, we identified the
transgelin (tagln) gene as a novel immediate target of
TGF-beta/Smad3-dependent gene expression in ATII cells using a Smad3
chromatin immunoprecipitation (ChIP) screen. Direct ChIP confirmed the rapid and specific binding of Smad3 to the tagln promoter.
Luciferase assays demonstrated transactivation of the tagln promoter by
activin-like
kinase (Alk) 5-mediated
TGF-beta signaling.
TGF-beta treatment resulted in rapid up-regulation of tagln, but not tagln2,
mRNA and
protein expression, assessed by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and immunofluorescence. In vivo, tagln expression was significantly increased in ATII cells of mice during
bleomycin-induced lung
fibrosis, as well as in lung specimen obtained from IPF patients, as assessed by RT-PCR and immunohistochemistry. Knockdown of tagln using
siRNA inhibited
TGF-beta-induced migration of lung epithelial A549 cells, as well as primary ATII cells. We thus identified tagln as a novel target of
TGF-beta/Smad3-dependent gene expression in ATII cells. Increased ATII cell expression of tagln in experimental and
idiopathic pulmonary fibrosis may contribute to
TGF-beta-dependent ATII cell injury, repair, and migration in lung
fibrosis.