Abrogation of TGF-beta1-induced fibroblast-myofibroblast differentiation by histone deacetylase inhibition

Am J Physiol Lung Cell Mol Physiol. 2009 Nov;297(5):L864-70. doi: 10.1152/ajplung.00128.2009. Epub 2009 Aug 21.


Idiopathic pulmonary fibrosis (IPF) is a devastating disease with no known effective pharmacological therapy. The fibroblastic foci of IPF contain activated myofibroblasts that are the major synthesizers of type I collagen. Transforming growth factor (TGF)-beta1 promotes differentiation of fibroblasts into myofibroblasts in vitro and in vivo. In the current study, we investigated the molecular link between TGF-beta1-mediated myofibroblast differentiation and histone deacetylase (HDAC) activity. Treatment of normal human lung fibroblasts (NHLFs) with the pan-HDAC inhibitor trichostatin A (TSA) inhibited TGF-beta1-mediated alpha-smooth muscle actin (alpha-SMA) and alpha1 type I collagen mRNA induction. TSA also blocked the TGF-beta1-driven contractile response in NHLFs. The inhibition of alpha-SMA expression by TSA was associated with reduced phosphorylation of Akt, and a pharmacological inhibitor of Akt blocked TGF-beta1-mediated alpha-SMA induction in a dose-dependent manner. HDAC4 knockdown was effective in inhibiting TGF-beta1-stimulated alpha-SMA expression as well as the phosphorylation of Akt. Moreover, the inhibitors of protein phosphatase 2A and 1 (PP2A and PP1) rescued the TGF-beta1-mediated alpha-SMA induction from the inhibitory effect of TSA. Together, these data demonstrate that the differentiation of NHLFs to myofibroblasts is HDAC4 dependent and requires phosphorylation of Akt.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Cell Differentiation / drug effects*
  • Cell Line, Transformed
  • Collagen / metabolism
  • Enzyme Activation / drug effects
  • Fibroblasts / cytology*
  • Fibroblasts / drug effects*
  • Fibroblasts / enzymology
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Muscle Contraction / drug effects
  • Muscle, Smooth / metabolism
  • Myoblasts / cytology*
  • Myoblasts / drug effects
  • Phenotype
  • Phosphorylation / drug effects
  • Protein Phosphatase 1 / antagonists & inhibitors
  • Protein Phosphatase 2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Repressor Proteins / antagonists & inhibitors*
  • Repressor Proteins / metabolism
  • Transforming Growth Factor beta1 / pharmacology*


  • Actins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Repressor Proteins
  • Transforming Growth Factor beta1
  • trichostatin A
  • Collagen
  • Proto-Oncogene Proteins c-akt
  • Protein Phosphatase 1
  • Protein Phosphatase 2
  • HDAC4 protein, human
  • Histone Deacetylases