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


ABSTRACT: 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.

SUBMITTER: Guo W 

PROVIDER: S-EPMC2777501 | biostudies-other | 2009 Nov

REPOSITORIES: biostudies-other

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

Guo Weichao W   Shan Bin B   Klingsberg Ross C RC   Qin Xiangmei X   Lasky Joseph A JA  

American journal of physiology. Lung cellular and molecular physiology 20090821 5


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.  ...[more]

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