Transforming growth factor β1-mediated activation of the smooth muscle α-actin gene in human pulmonary myofibroblasts is inhibited by tumor necrosis factor-α via Mitogen-activated protein kinase kinase 1-dependent induction of the egr-1 transcriptional repressor

Xiaoying Liu, Robert J. Kelm, Arthur R. Strauch

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Transforming growth factor (TGF) β1 is a mediator of myofibroblast differentiation in healing wounds in which it activates transcription of the smooth muscle a-actin (SMaA) gene via dynamic interplay of nuclear activators and repressors. Targeting components of TGFβ1 signaling may be an effective strategy for controlling myofibroblasts in chronic fibrotic diseases. We examined the ability of proinflammatory tumor necrosis factor (TNF)-a to antagonize TGFβ1-mediated human pulmonary myofibroblast differentiation. TNF-α abrogated TGFβ1-induced SMaA gene expression at the level of transcription without disrupting phosphorylation of regulatory Smads. Intact mitogen-activated protein kinase kinase (Mek)-extracellular signal-regulated kinase (Erk) kinase signaling was required for myofibroblast repression by TNF-α via induction of the early growth response factor-1 (Egr-1) DNA-binding protein. Egr-1 bound to the GC-rich SPUR activation element in the SMaA promoter and potently suppressed Smad3-and TGFβ1-mediated transcription. Reduction in Smad binding to the SMaA promoter in TNF-α-treated myofibroblasts was accompanied by an increase in Egr-1 and YB-1 repressor binding, suggesting that the molecular mechanism underlying repression may involve competitive interplay between Egr-1, YB-1, and Smads. The ability of TNF-a to attenuate myofibroblast differentiation via modulation of a Mek1/Erk/Egr-1 regulatory axis may be useful in designing new therapeutic targets to offset destructive tissue remodeling in chronic fibrotic disease.

Original languageEnglish (US)
Pages (from-to)2174-2185
Number of pages12
JournalMolecular biology of the cell
Volume20
Issue number8
DOIs
StatePublished - Apr 15 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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