TUMOUR NECROSIS FACTOR α (TNF-α) 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-α THERAPY FOR RA

• Published in: Cytokine (Philadelphia, Pa.) Vol. 12; no. 3; pp. 281 - 288
• Main Authors: Ohshima, Shiro, Mima, Toru, Sasai, Mitsuko, Nishioka, Katsuhiro, Shimizu, Masatoshi, Murata, Norikazu, Yoshikawa, Hiroo, Nakanishi, Katsuyuki, Suemura, Masaki, McCloskey, Richard V, Kishimoto, Tadamitsu, Saeki, Yukihiko
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.03.2000
• Subjects: Antibodies, Monoclonal - therapeutic use; Apoptosis; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; fas Receptor - biosynthesis; fas Receptor - physiology; Female; Humans; Hyperplasia - pathology; Infliximab; Middle Aged; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; RA/synovial hyperplasia/TNF-α/Fas/apoptosis; Synovial Membrane - metabolism; Synovial Membrane - pathology; Tumor Necrosis Factor-alpha - metabolism; RA/synovial hyperplasia/TNF-α/Fas/apoptosis
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1006/cyto.1999.0552

To investigate the mechanism of rheumatoid synovial hyperplasia (RASH), the influence of tumour necrosis factor α (TNF-α) 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-α on Fas-ACD, SCs were cultured with anti-Fas antibody (CH11) for 16h in the absence or presence of different doses of recombinant TNF-α. 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-α interfered with Fas-ACD on RASCs in a dose-dependent manner. Moreover, removal of TNF-α activity by a neutralizing anti-TNF-α 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 TNFα. These results suggest the following: (1) Fas-ACD might be diminished in vivo by local excessive TNF-α and this might contribute in part to RASH. (2) The inhibition of Fas-ACD on RASCs by TNF-α 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-α activity could restore Fas-ACD in RA synovium, implicating a clinical benefit of anti-TNF-α therapy for RA.