Anti-DR5 mAb ameliorate adjuvant arthritis rats through inducing synovial cells apoptosis.
OBJECTIVE
Study the therapeutic effects and immunoregulatory mechanisms of anti-DR5 mAb on adjuvant arthritis (AA) rats.


METHODS
AA rats induced by CFA, were treated with anti-DR5 mAb through mainline administration. Effect on the synovial membranes of the tissues was detected by H&E staining. Flow cytometry and MTT assay were used for detecting the induced apoptosis in an in vitro system and TUNEL assay was used for analysis in an in vivo system. The involvement of the apoptotic pathway was further proved by a caspase inhibition assay.


RESULTS
Anti-DR5 mAb could induce synovial cell apoptosis in an in vitro system, which was related with the mRNA expression of DR5 on the cell surface. The mRNA expressions of c-myc and bcl-2 were decreased in synovial cells and those of p21, p53, and bax were increased. The protein expressions of caspase-8/3/9, RANKL, JNK2, and c-Jun were raised and that of bcl-2 was decreased. When the caspase inhibitor was added to the synovial cells treated with anti-DR5 mAb, it showed a dose-dependence inhibition effect, indicating that anti-DR5 mAb inducing apoptosis might be through the caspase pathway.


CONCLUSIONS
This study shows that anti-DR5 mAb can ameliorate arthritic symptoms. The mechanisms of the treatment are related to the increase in synovial cell apoptosis by regulating the mRNA expression of DR5 and apoptosis-related genes, prolonging the duration of the cell cycle by modulation of the mRNA expression of cell cycle-related genes, and the protein expression of the molecules in the caspase pathway and RANKL, JNK2, and c-Jun.
Li
Wenzhu
W
Anti-Cancer Research Center, Medical College, Xiamen University, 422 SiMing South Road, Xiamen 361005, Fujian, China.
Liu
Zhongchen
Z
Zhuang
Guohong
G
Yin
Ping
P
Tao
Huiran
H
Qiu
Jinghua
J
Hu
Qingzhong
Q
Zhang
Jiakai
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D020169:Caspases / Q000096:biosynthesis / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D016259:Genes, myc / Q000276:immunology; D008297:Male; D048056:Mitogen-Activated Protein Kinase 9 / Q000096:biosynthesis / Q000276:immunology; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000276:immunology; D053245:RANK Ligand / Q000096:biosynthesis / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000276:immunology*; D013582:Synovial Fluid / Q000276:immunology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000276:immunology; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000276:immunology
D000911:Antibodies, Monoclonal; C494828:Bax protein, rat; D016755:Proto-Oncogene Proteins c-jun; D053245:RANK Ligand; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D048056:Mitogen-Activated Protein Kinase 9; D020169:Caspases