Tumour necrosis factor alpha (TNF-alpha) interferes with Fas-mediated apoptotic cell death on rheumatoid arthritis (RA) synovial cells: a possible mechanism of rheumatoid synovial hyperplasia and a clinical benefit of anti-TNF-alpha therapy for RA

Cytokine. 2000 Mar;12(3):281-8. doi: 10.1006/cyto.1999.0552.


To investigate the mechanism of rheumatoid synovial hyperplasia (RASH), the influence of tumour necrosis factor alpha (TNF-alpha) on Fas-mediated apoptotic cell death (Fas-ACD) was examined on cultured rheumatoid synovial cells (RASCs). RASCs were obtained from the synovial tissues of eight patients with rheumatoid arthritis (RA) and SCs from eight patients with osteoarthritis (OA) were used as a control. To examine the influence of TNF-alpha on Fas-ACD, SCs were cultured with anti-Fas antibody (CH11) for 16 h in the absence or presence of different doses of recombinant TNF-alpha. ACD was determined by electron microscopic analysis and the percentage of apoptotic cells was calculated by trypan blue staining. In addition, the expression of Fas and Bcl-2 on RASCs was examined by flow cytometry. As a result, RASCs were more susceptible to Fas-ACD in vitro than OASCs. TNF-alpha interfered with Fas-ACD on RASCs in a dose-dependent manner. Moreover, removal of TNF-alpha activity by a neutralizing anti-TNF-alpha antibody (cA2) restored Fas-ACD. Flow cytometric analysis showed no significant changes in either Fas or Bcl-2 expression on RASCs after the culture with TNFalpha. These results suggest the following: (1) Fas-ACD might be diminished in vivo by local excessive TNF-alpha and this might contribute in part to RASH. (2) The inhibition of Fas-ACD on RASCs by TNF-alpha might not be associated with changes in the expression of Fas or Bcl-2. (3) In addition, considering a magnetic resonance imaging (MRI) finding of marked reduction in the RASH after cA2 treatment, blockade of TNF-alpha activity could restore Fas-ACD in RA synovium, implicating a clinical benefit of anti-TNF-alpha therapy for RA.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / therapeutic use
  • Apoptosis
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology*
  • Female
  • Humans
  • Hyperplasia / pathology
  • Infliximab
  • Middle Aged
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology*
  • Tumor Necrosis Factor-alpha / metabolism*
  • fas Receptor / biosynthesis
  • fas Receptor / physiology*


  • Antibodies, Monoclonal
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Infliximab