Importance of NF-κB in rheumatoid synovial tissues: in situ NF-κB expression and in vitro study using cultured synovial cells

• Published in: Annals of the rheumatic diseases Vol. 60; no. 7; pp. 678 - 684
• Main Authors: Yamasaki, S, Kawakami, A, Nakashima, T, Nakamura, H, Kamachi, M, Honda, S, Hirai, Y, Hida, A, Ida, H, Migita, K, Kawabe, Y, Koji, T, Furuichi, I, Aoyagi, T, Eguchi, K
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd and European League Against Rheumatism 01.07.2001; BMJ
• Subjects: apoptosis; Biological and medical sciences; Diseases of the osteoarticular system; Extended Report; Inflammatory joint diseases; interleukin 1β; Medical sciences; NF-κB; rheumatoid arthritis; tumour necrosis factor α; Human; Immunohistochemistry; Immunopathology; Cell culture; Immune response; Pathogenesis; Cytokine; Diseases of the osteoarticular system; Autoimmune disease; Interleukin 1β; Inflammatory joint disease; Monoclonal antibody; Gene expression; In vitro; Pathology; Chronic; Histopathology; Synovial membrane; Cell death; Rheumatoid arthritis; Transcription factor NFκB; Tumor necrosis factor α; Apoptosis
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/ard.60.7.678

OBJECTIVES To examine whether inhibition of NF-κB induces apoptosis of human synovial cells stimulated by tumour necrosis factor α (TNFα), interleukin 1β (IL1β), and anti-Fas monoclonal antibody (mAb). METHODS The expression of proliferating cell nuclear antigen (PCNA), NF-κB, and the presence of apoptotic synovial cells were determined in synovial tissues. Apoptosis of cultured synovial cells was induced by inhibition of NF-κB nuclear translocation by Z-Leu-Leu-Leu-aldehyde (LLL-CHO). The activation of caspase-3 and expression of XIAP and cIAP2 in synovial cells in LLL-CHO induced apoptosis was also examined. RESULTS Abundant PCNA+ synovial cells were found in rheumatoid arthritis (RA) synovial tissue, though a few apoptotic synovial cells were also detected in the RA synovial tissues. Nuclear NF-κB was expressed in RA synovial cells. Electrophoretic mobility shift assay showed that treatment of cells with TNFα or IL1β significantly stimulated nuclear NF-κB activity. A small number of apoptotic synovial cells expressing intracellular active caspase-3 were found after treatment of cells with LLL-CHO. Although treatment of RA synovial cells with TNFα or IL1β alone did not induce apoptosis, apoptosis induced by LLL-CHO and caspase-3 activation were clearly enhanced in TNFα or IL1β stimulated synovial cells compared with unstimulated synovial cells. Furthermore, induction of apoptosis of synovial cells with caspase-3 activation by anti-Fas mAb was clearly increased by LLL-CHO. The expression of cIAP2 and XIAP in synovial cells may not directly influence the sensitivity of synovial cells to apoptosis induced by LLL-CHO. CONCLUSION The results suggest that NF-κB inhibition may be a potentially important therapeutic approach for RA by correcting the imbalance between apoptosis and proliferation of synovial cells in RA synovial tissue.