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Published ahead of print on January 16, 2009, doi:10.1165/rcmb.2008-0288OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 41, pp. 332-338, 2009
© 2009 American Thoracic Society
DOI: 10.1165/rcmb.2008-0288OC

Critical Role of Serum Response Factor in Pulmonary Myofibroblast Differentiation Induced by TGF-β

Nathan Sandbo1, Steven Kregel1, Sebastien Taurin1, Sangeeta Bhorade1 and Nickolai O. Dulin1

1 Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois

Correspondence and requests for reprints should be addressed to Nathan Sandbo, M.D., Section of Pulmonary and Critical Care Medicine, University of Chicago, 5841 S. Maryland Ave., MC 6076, Chicago, IL 60618. E-mail: nsandbo{at}medicine.bsd.uchicago.edu or ndulin{at}medicine.bsd.uchicago.edu

Transforming growth factor-β (TGF-β) is a cytokine implicated in wound healing and in the pathogenesis of pulmonary fibrosis. TGF-β stimulates myofibroblast differentiation characterized by expression of contractile smooth muscle (SM)-specific proteins such as SM–{alpha}-actin. In the present study, we examined the role of serum response factor (SRF) in the mechanism of TGF-β–induced pulmonary myofibroblast differentiation of human lung fibroblasts (HLF). TGF-β stimulated SM–{alpha}-actin expression in HLF, which paralleled with a profound induction of SRF expression and activity. Inhibition of SRF by the pharmacologic SRF inhibitor (CCG-1423), or via adenovirus-mediated transduction of SRF short hairpin RNA (shSRF), blocked the expression of both SRF and SM–{alpha}-actin in response to TGF-β without affecting Smad-mediated signaling of TGF-β. However, forced expression of SRF on its own did not promote SM–{alpha}-actin expression, whereas expression of the constitutively transactivated SRF fusion protein (SRF-VP16) was sufficient to induce SM–{alpha}-actin expression, suggesting that both expression and transactivation of SRF are important. Activation of protein kinase A (PKA) by forskolin or iloprost resulted in a significant inhibition of SM–{alpha}-actin expression induced by TGF-β, and this was associated with inhibition of both SRF expression and activity, but not of Smad-mediated gene transcription. In summary, this is the first direct demonstration that TGF-β–induced pulmonary myofibroblast differentiation is mediated by SRF, and that inhibition of myofibroblast differentiation by PKA occurs through down-regulation of SRF expression levels and SRF activity, independent of Smad signaling.

Key Words: transforming growth factor-β • serum response factor • myofibroblast • protein kinase A • Smad


CLINICAL RELEVANCE

This study demonstrates the important role of serum response factor in mediating pulmonary myofibroblast differentiation by transforming growth factor-β. Inhibition of serum response factor may be a useful strategy for treating pulmonary fibrosis.

 





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