Epirubicin potentiates recombinant adeno‐associated virus type 2/5–mediated TRAIL expression in fibroblast‐like synoviocytes and augments the antiarthritic effects of rAAV2/5‐TRAIL

表阿霉素 癌症研究 体内 医学 流式细胞术 药理学 免疫学 化学 化疗 生物 内科学 环磷酰胺 生物技术
作者
Juan Shi,Zhijuan Diao,Jiaolin Zhou,Jieqing Zhu,Haiqin Yuan,Xin You,Yanxin Liu,Dexian Zheng
出处
期刊:Arthritis & Rheumatism [Wiley]
卷期号:64 (5): 1345-1354 被引量:13
标识
DOI:10.1002/art.33492
摘要

Abstract Objective Synovial cells in rheumatoid synovium display abnormal proliferation, which leads to joint destruction. TRAIL has been described as a proapoptotic factor in fibroblast‐like synoviocytes (FLS). This study was undertaken to investigate the functions of rAAV2/5‐TRAIL in human FLS and in arthritic mice. Methods Primary human FLS were infected with rAAV2/5‐TRAIL in the presence or absence of epirubicin. Transgene expression was monitored by both enzyme‐linked immunosorbent assay and flow cytometry. The disease‐modulating activity of epirubicin plus rAAV2/5‐TRAIL was investigated in mice with collagen‐induced arthritis (CIA). Results Subtoxic doses of epirubicin potentiated rAAV2/5‐mediated TRAIL expression in FLS and simultaneously enhanced the sensitivity of FLS to TRAIL. Epirubicin treatment up‐regulated death receptor 4 (DR‐4) and DR‐5 expression and down‐regulated FLIP expression, thereby enhancing the activation of procaspase 3, procaspase 8, and procaspase 9. An in vivo study showed that the combination of rAAV2/5‐TRAIL gene therapy and epirubicin chemotherapy provided augmented antiarthritic effects in a mouse model of CIA. The intraarticular injection of rAAV2/5‐TRAIL combined with epirubicin treatment significantly reduced the severity and incidence of CIA and joint swelling in the animals. Histologic evaluations revealed that inflammatory cell infiltration, cartilage destruction, and bone erosion were significantly reduced in the joints of the mice receiving the synthetic treatment. Results of a viral genome copy number assay indicated that epirubicin dramatically augmented the expression of rAAV2/5‐TRAIL without altering its tissue distribution. Conclusion These results suggest that epirubicin enhances the antiarthritic effect of rAAV2/5‐TRAIL and that combination treatment might be an important therapeutic alternative, with practical significance for rheumatoid arthritis.

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