TRAIL-R2 (DR5) Mediates Apoptosis of Synovial Fibroblasts in Rheumatoid Arthritis

• Published in: The Journal of immunology (1950) Vol. 171; no. 2; pp. 1061 - 1069
• Main Authors: Ichikawa, Kimihisa, Liu, Weimin, Fleck, Martin, Zhang, Huangge, Zhao, Limin, Ohtsuka, Toshiaki, Wang, Zheng, Liu, Di, Mountz, John D, Ohtsuki, Masahiko, Koopman, William J, Kimberly, Robert, Zhou, Tong
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.07.2003
• Subjects: Adult; Aged; Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Apoptosis - immunology; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Arthritis, Rheumatoid - prevention & control; Cell Line; Disease Models, Animal; Female; Fibroblasts - immunology; Fibroblasts - metabolism; Fibroblasts - pathology; Fibroblasts - transplantation; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; NF-kappa B - metabolism; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor - biosynthesis; Receptors, Tumor Necrosis Factor - immunology; Receptors, Tumor Necrosis Factor - physiology; Synovial Membrane - immunology; Synovial Membrane - metabolism; Synovial Membrane - pathology; Synovial Membrane - transplantation; Transcriptional Activation - immunology; Transplantation, Heterologous - immunology; Transplantation, Heterologous - pathology; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.171.2.1061

TRAIL has been proposed as an anti-inflammatory cytokine in animal models of rheumatoid arthritis (RA). Using two agonistic mAbs specific for TRAIL-R1 (DR4) and TRAIL-R2 (DR5), we examined the expression and function of these death receptors in RA synovial fibroblast cells. The synovial tissues and primary synovial fibroblast cells isolated from patients with RA, but not those isolated from patients with osteoarthritis, selectively expressed high levels of cell surface DR5 and were highly susceptible to anti-DR5 Ab (TRA-8)-mediated apoptosis. In contrast, RA synoviocytes did not show increased expression of TRAIL-R1 (DR4), nor was there any difference in expression of Fas between RA and osteoarthritis synovial cells. In vitro TRA-8 induced apoptosis of RA synovial cells and inhibited production of matrix metalloproteinases induced by pro-inflammatory cytokines. In vivo TRA-8 effectively inhibited hypercellularity of a SV40-transformed RA synovial cell line and completely prevented bone erosion and cartilage destruction induced by these cells. These results indicate that increased DR5 expression and susceptibility to DR5-mediated apoptosis are characteristic of the proliferating synovial cells in RA. As highly proliferative transformed-appearing RA synovial cells play a crucial role in bone erosion and cartilage destruction in RA, the specific targeting of DR5 on RA synovial cells with an agonistic anti-DR5 Ab may be a potential therapy for RA.