Effect of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand on the Reduction of Joint Inflammation in Experimental Rheumatoid Arthritis

This study focused on the potential therapeutic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on collagen-induced arthritis (CIA) and on the elucidation of the mechanisms involved. DBA/1J mice with established CIA were treated with various amount of recombinant soluble human TRAIL. The effects of TRAIL on the development and severity of CIA in this DBA/1J mouse model were assessed clinically and histologically, and a detailed investigation was conducted on proinflammatory cytokine and anticollagen-specific antibody levels. Cellular immunity was evaluated by investigating the proliferative responses and cytokine release profiles of splenocytes after TRAIL treatment. TRAIL treatment significantly reduced the severity and incidence of CIA, joint swelling, erythema, and edema. Histologic evaluations revealed that inflammatory cell infiltration, cartilage destruction, and bone erosion were significantly reduced in joints of TRAIL-treated mice with dose-dependent manner. TRAIL treatment also strongly decreased and/or normalized the productions of proinflammatory cytokines and of anti-collagen-specific antibodies in the sera of CIA mice. Furthermore, in vitro studies with primary splenocytes showed the cytotoxic effect of TRAIL on activated lymphocytes, with reduction of inflammatory cytokine release. These findings show that TRAIL administration is an effective anti-inflammatory treatment that prevents the development and progression of CIA in DBA/1J mice, and they suggest that TRAIL might be considered a potential treatment for human RA.Youn YS, 2007, BIOTECHNOL LETT, V29, P713, DOI 10.1007/s10529-006-9300-7Martinez-Lorenzo MJ, 2007, CLIN IMMUNOL, V122, P28, DOI 10.1016/j.clim.2006.07.007Yao QP, 2006, ARTHRITIS RES THER, V8, DOI 10.1186/ar1867Borchers AT, 2004, SEMIN ARTHRITIS RHEU, V34, P465, DOI 10.1016/j.semarthrit.2003.12.003Evans CH, 2004, GENE THER, V11, P735, DOI 10.1038/sj.gt.3302256Li EK, 2004, CLIN THER, V26, P447Liu ZG, 2003, J CLIN INVEST, V112, P1332, DOI 10.1172/JCI2003219209Tsokos GC, 2003, J CLIN INVEST, V112, P1315, DOI 10.1172/JCI200320297Brand DD, 2003, SPRINGER SEMIN IMMUN, V25, P3, DOI 10.1007/s00281-003-0127-1Lamhamedi-Cherradi SE, 2003, NAT IMMUNOL, V4, P255, DOI 10.1038/ni894Mackay F, 2002, CURR OPIN IMMUNOL, V14, P783Genovese MC, 2002, ARTHRITIS RHEUM, V46, P1443, DOI 10.1002/art.10308Lunemann JD, 2002, J IMMUNOL, V168, P4881Luross JA, 2001, IMMUNOLOGY, V103, P407Lipsky PE, 2000, NEW ENGL J MED, V343, P1594Song KM, 2000, J EXP MED, V191, P1095Ashkenazi A, 1999, CURR OPIN CELL BIOL, V11, P255Griffith TS, 1998, CURR OPIN IMMUNOL, V10, P559Ashkenazi A, 1998, SCIENCE, V281, P1305Emery JG, 1998, J BIOL CHEM, V273, P14363Marsters SA, 1997, CURR BIOL, V7, P1003Chaudhary PM, 1997, IMMUNITY, V7, P821Walczak H, 1997, EMBO J, V16, P5386Cohen GM, 1997, BIOCHEM J, V326, P1Pan GH, 1997, SCIENCE, V277, P815Gura T, 1997, SCIENCE, V277, P768Pan GH, 1997, SCIENCE, V276, P111Campion GV, 1996, ARTHRITIS RHEUM, V39, P1092Feldmann M, 1996, CELL, V85, P307Smolen JS, 1996, SCAND J RHEUMATOL, V25, P1Wiley SR, 1995, IMMUNITY, V3, P673SCHNABEL A, 1994, SEMIN ARTHRITIS RHEU, V23, P310PANAYI GS, 1992, ARTHRITIS RHEUM, V35, P729FIRESTEIN GS, 1990, ARTHRITIS RHEUM, V33, P768HARRIS ED, 1990, NEW ENGL J MED, V322, P1277