Antagonistic effects of TNF-alpha on TGF-beta signaling through down-regulation of TGF-beta receptor type II in human dermal fibroblasts

J Immunol. 2003 Oct 1;171(7):3855-62. doi: 10.4049/jimmunol.171.7.3855.


Transforming growth factor-beta stimulates the production of the extracellular matrix, whereas TNF-alpha has antifibrotic activity. Understanding the molecular mechanism underlying the antagonistic activities of TNF-alpha against TGF-beta is critical in the context of tissue repair and maintenance of tissue homeostasis. In the present study, we demonstrated a novel mechanism by which TNF-alpha blocks TGF-beta-induced gene and signaling pathways in human dermal fibroblasts. We showed that TNF-alpha prevents TGF-beta-induced gene trans activation, such as alpha2(I) collagen or tissue inhibitor of metalloproteinases 1, and TGF-beta signaling pathways, such as Smad3, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases, without inducing levels of inhibitory Smad7 in human dermal fibroblasts. TNF-alpha down-regulates the expression of type II TGF-beta receptor (TbetaRII) proteins, but not type I TGF-beta receptor (TbetaRI), in human dermal fibroblasts. However, neither TbetaRII mRNA nor TbetaRII promoter activity was decreased by TNF-alpha. TNF-alpha-mediated decrease of TbetaRII protein expression was not inhibited by the treatment of fibroblasts with either a selective inhibitor of I-kappaB-alpha phosphorylation, BAY 11-7082, or a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, PD98059. Calpain inhibitor I (ALLN), a protease inhibitor, inhibits TNF-alpha-mediated down-regulation of TbetaRII. We found that TNF-alpha triggered down-regulation of TbetaRII, leading to desensitization of human dermal fibroblasts toward TGF-beta. Furthermore, these events seemed to cause a dramatic down-regulation of alpha2(I) collagen and tissue inhibitor of metalloproteinases 1 in systemic sclerosis fibroblasts. These results indicated that TNF-alpha impaired the response of the cells to TGF-beta by regulating the turnover of TbetaRII.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • DNA-Binding Proteins / biosynthesis
  • Down-Regulation / genetics
  • Down-Regulation / physiology*
  • Extracellular Matrix / genetics
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / pathology
  • Extracellular Matrix / physiology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibroblasts / physiology*
  • Gene Expression Regulation / physiology
  • Humans
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Receptors, Transforming Growth Factor beta / biosynthesis
  • Scleroderma, Systemic / genetics
  • Scleroderma, Systemic / metabolism
  • Scleroderma, Systemic / pathology
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Skin Physiological Phenomena*
  • Smad7 Protein
  • Trans-Activators / biosynthesis
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Transforming Growth Factor beta / physiology*
  • Tumor Necrosis Factor-alpha / physiology*


  • DNA-Binding Proteins
  • Receptors, Transforming Growth Factor beta
  • SMAD7 protein, human
  • Smad7 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II