Tumor necrosis factor-alpha inhibits transforming growth factor-beta /Smad signaling in human dermal fibroblasts via AP-1 activation

J Biol Chem. 2000 Sep 29;275(39):30226-31. doi: 10.1074/jbc.M005310200.


Understanding the molecular mechanisms underlying the antagonistic activities of tumor necrosis factor-alpha (TNF-alpha) against transforming growth factor-beta (TGF-beta) is of utmost importance given the physiopathological implications of these cytokines. In this report, we demonstrate that TNF-alpha prevents TGF-beta-induced Smad-specific gene transactivation without inducing detectable levels of inhibitory Smad7 in human dermal fibroblasts. On the other hand, c-Jun and JunB, both induced by TNF-alpha, block Smad3-mediated transcription. Expression of antisense c-Jun mRNA prevents TNF-alpha inhibition of TGF-beta/Smad signaling whereas that of dominant-negative Ikappa-B kinase-alpha or antisense Smad7 does not. We provide evidence for off-DNA interactions between Smad3 and both c-Jun and JunB accompanied with reduced Smad3-DNA interactions. Finally, we show that overexpression of the transcriptional co-activator p300 prevents TNF-alpha/AP-1 inhibition of TGF-beta/Smad signaling. These data suggest that TNF-alpha interferes with Smad signaling through the induction of AP-1 components, the latter forming off-DNA complexes with Smad3 and preventing its binding to specific cis-element(s). In addition, Jun members compete with Smad3 for the common transcription co-activator p300. These two mechanisms are likely to act in concert to decrease Smad-specific transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Dermis / cytology
  • Dermis / metabolism
  • Drug Antagonism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • I-kappa B Kinase
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • RNA, Antisense / pharmacology
  • Signal Transduction
  • Smad3 Protein
  • Smad7 Protein
  • Trans-Activators / metabolism*
  • Transcription Factor AP-1 / metabolism*
  • Transcriptional Activation*
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Necrosis Factor-alpha / pharmacology*


  • DNA-Binding Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-jun
  • RNA, Antisense
  • SMAD3 protein, human
  • SMAD7 protein, human
  • Smad3 Protein
  • Smad7 Protein
  • Trans-Activators
  • Transcription Factor AP-1
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Protein Serine-Threonine Kinases
  • CHUK protein, human
  • I-kappa B Kinase
  • IKBKB protein, human
  • IKBKE protein, human