title: The pro-apoptotic effects of TIPE2 on AA rat fibroblast-like synoviocytes via regulation of the DR5-caspase-NF-κB pathway in vitro.
abstract: TIPE2, also known as TNFAIP8L2, a member of the tumor necrosis factor-alpha-induced protein-8 (TNFAIP8) family, is known as an inhibitor in inflammation and cancer, and its overexpression induces cell death. We examined the role of TIPE2 with respect to adjuvant arthritis (AA)-associated pathogenesis by analyzing the TIPE2 regulation of death receptor (DR5)-mediated apoptosis in vitro. The results showed that TIPE2 was detected in normal fibroblast-like synoviocytes (FLSs), but scarcely observed in AA-FLSs. Therefore, recombinant MIGR1/TIPE2(+/+) and control MIGR1 lentivirus vectors were transfected to AA-FLSs, which were denoted as TIPE2(+/+)-FLSs and MIGR1-FLSs, respectively. Our results showed that TIPE2(+/+)-FLSs were highly susceptible to ZF1-mediated apoptosis, and ZF1 was our own purification of an anti-DR5 single chain variable fragment antibody. Under the presence of TIPE2, the expression of DR5 was significantly increased compared with that of the MIGR1-FLS group. In contrast, the level of phosphorylated nuclear factor-kappa B (pNF-κB) was lower in the TIPE2(+/+)-FLS group treated with ZF1, whereas the activity of caspase was higher. Moreover, the rate of apoptosis in the TIPE2(+/+)-FLS group, which was pretreated with caspase inhibitor Z-VAD-FMK, was significantly decreased. In contrast, the apoptosis occurrence in the MIGR1-FLS group increased significantly with the pretreatment of the NF-κB inhibitor Bay. These results indicated that TIPE2 increased the apoptosis of AA-FLSs by enhancing DR5 expression levels, thereby promoting the activation of caspase and inhibiting the activation of NF-κB in AA-FLSs. TIPE2 might potentially act as a therapeutic target for rheumatoid arthritis.
authors.affiliation: Organ Transplantation Institute, Anti-Cancer Research Center, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China; The Department of Oncology, Jiujiang No. 1 People's Hospital, Jiujiang, Jiangxi City, People's Republic of China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Shi
authors.affiliation: Organ Transplantation Institute, Anti-Cancer Research Center, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China; Division of Gastroenterology Surgery, Zhongshan Hospital, Gastroenterology Institute of Xiamen University, Gastroenterology Center of Xiamen, Xiamen, Fujian, People's Republic of China.
authors.forename: Shifeng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Organ Transplantation Institute, Anti-Cancer Research Center, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Shifu
authors.initials: S
authors.lastname: Hong
authors.affiliation: Organ Transplantation Institute, Anti-Cancer Research Center, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Jinglong
authors.initials: J
authors.lastname: Pang
authors.affiliation: Organ Transplantation Institute, Anti-Cancer Research Center, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Yeletai
authors.initials: Y
authors.lastname: Yesibulati
authors.affiliation: The Department of Pathology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yin
authors.affiliation: Organ Transplantation Institute, Anti-Cancer Research Center, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Zhuang
keywords: DR5; TIPE2; adjuvant arthritis; fibroblast-like synoviocytes; rheumatoid arthritis