Transforming growth factor beta 1(TGF-beta1) down-regulates TNFalpha-induced RANTES production in rheumatoid synovial fibroblasts through NF-kappaB-mediated transcriptional repression

Immunol Lett. 2006 Jun 15;105(2):159-66. doi: 10.1016/j.imlet.2006.02.003. Epub 2006 Mar 3.


Transforming growth factor (TGF)-beta1 is a pleiotropic cytokine with many functions, including those related to growth modulation, immunosuppression, and pro-inflammation, in a wide variety of cell types. In this study, we investigated the ability of TGF-beta1 to regulate RANTES production by activated rheumatoid synovial fibroblasts. Fibroblast-like synoviocytes (FLS) were cultured in the presence of TGF-beta1 and IL-1beta, IL-15, TNFalpha, or IL-17, and the secretion of RANTES into culture supernatants was measured by enzyme-linked immunosorbent assay (ELISA). Expression of RANTES encoded mRNA was determined by reverse transcription-polymerase chain reaction (RT-PCR), and NF-kappaB binding activity for RANTES transcription was determined by electrophoretic mobility shift assay (EMSA). We found that the concentrations of RANTES in synovial fluid (SF) from rheumatoid arthritis (RA) patients were lower than in SF from osteoarthritis (OA) patients, whereas the concentrations of TGF-beta1 were higher in RA SF than in OA SF. TGF-beta1 dose-dependently inhibited TNFalpha-induced production of RANTES protein and mRNA from RA FLS. Addition of RA SF with high-level TGF-beta1 mimicked the effect of TGF-beta1 on TNFalpha-induced RANTES production, which was inhibited by treatment with anti-TGF-beta1 neutralizing antibody. TGF-beta1 blocked the degradation of cytosolic IkappaB-alpha and the translocation of activated NF-kappaB to the nucleus. EMSA showed that the inhibitory effect of TGF-beta1 was associated with decreased binding of NF-kappaB to the RANTES promoter. These results suggest that elevated TGF-beta1 in rheumatoid synovial tissue may suppress joint inflammation by inhibiting RANTES secretion from synovial fibroblasts, thus blocking the infiltration of immune cells. These findings may provide an explanation for the mechanism by which TGF-beta1 regulates immune function in RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / metabolism*
  • Cells, Cultured
  • Chemokine CCL5 / biosynthesis*
  • Chemokine CCL5 / genetics
  • Down-Regulation / drug effects*
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Male
  • Middle Aged
  • NF-kappa B / metabolism*
  • Osteoarthritis / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • RNA, Messenger / genetics
  • Synovial Fluid / metabolism
  • Synovial Membrane / cytology*
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / genetics
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology*
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Chemokine CCL5
  • NF-kappa B
  • RNA, Messenger
  • TGFB1 protein, human
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha