Berberine Induces Dendritic Cell Apoptosis and Has Therapeutic Potential for Rheumatoid Arthritis
Berberine Induces Dendritic Cell Apoptosis and Has Therapeutic Potential for Rheumatoid Arthritis
复制标题
DOI：
10.1002/art.30202
复制
发表时间：
2011-04-01
影响因子：
--
通讯作者：
Zhang, Weidong
中科院分区：
文献类型：
--
作者：
Hu, Zhenlin;Jiao, Qing;Zhang, Weidong
Objective.目的探讨小檗碱对类风湿关节炎（RA）树突状细胞（DC）凋亡的影响及其作为RA治疗药物的可能性。通过分别用粒细胞-巨噬细胞集落刺激因子/白细胞介素-4或flt 3L培养骨髓（BM）衍生的髓样DC（MDC）和浆细胞样DC（PDC）来产生BM细胞。使用磁激活细胞分选系统纯化脾DC、T细胞和B细胞。通过膜联蛋白V/碘化丙啶或Hoechst 33258染色评估体外细胞凋亡。在胶原诱导的关节炎（CIA）小鼠体内观察小檗碱的作用。通过测定血清抗体水平、淋巴细胞增殖和细胞因子产生来确定针对II型胶原（CII）的免疫应答。采用流式细胞术和免疫组化技术检测脾脏和淋巴结中DC的比例及不同免疫细胞亚群的凋亡情况。骨髓细胞分化过程中MDCs暴露于小檗碱通过诱导凋亡减少细胞恢复。对小檗碱诱导的细胞凋亡的敏感性在DC分化的第3天开始获得，并且成熟的DC比未成熟的DC对小檗碱更敏感。小鼠腹腔巨噬细胞、RAW 264.7细胞和Jurkat细胞对小檗碱诱导的凋亡不敏感。脾脏DCs对小檗碱的敏感性高于T、B细胞。PDCs对小檗碱诱导的凋亡的敏感性与MDCs相似。在CIA小鼠中，小檗碱治疗可改善关节炎，抑制CII特异性免疫应答，并选择性增加脾脏和淋巴结内DCs凋亡的发生率。这些发现表明小檗碱选择性地诱导DC凋亡。因此，小檗碱可能是一种新的治疗RA的药物。
Objective. To investigate the effects of berberine on dendritic cell (DC) apoptosis and its potential as a therapeutic agent in rheumatoid arthritis (RA).Methods. Bone marrow (BM)-derived myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) were generated by culturing BM cells with granulocyte-macrophage colony-stimulating factor/interleukin-4 or flt3L, respectively. Splenic DCs, T cells, and B cells were purified using a magnetic-activated cell sorting system. In vitro apoptosis was assessed by annexin V/propidium iodide or Hoechst 33258 staining. The in vivo effects of berberine were examined in mice with collagen-induced arthritis (CIA). Immune responses against type II collagen (CII) were determined by assaying serum antibody levels, lymphocyte proliferation, and cytokine production. The proportions of DCs and apoptosis of different immune cell subsets in spleens and lymph nodes were analyzed by flow cytometry and immunohistochemistry after subset-specific surface marker labeling and TUNEL staining.Results. Exposure of MDCs to berberine during BM cell differentiation reduced cell recovery by inducing apoptosis. Sensitivity to berberine-induced apoptosis was acquired starting on day 3 of DC differentiation, and mature DCs were more sensitive to berberine than immature DCs. Murine peritoneal macrophages, RAW 264.7 cells, and Jurkat cells were insensitive to berberine-induced apoptosis. Splenic DCs were more sensitive to berberine than T and B cells. Susceptibility of PDCs to berberine-induced apoptosis was similar to that of MDCs. In mice with CIA, berberine treatment ameliorated arthritis, suppressed CII-specific immune responses, and selectively increased the incidence of apoptosis in DCs within spleens and lymph nodes.Conclusion. These findings show that berberine selectively induces apoptosis in DCs. Berberine may thus represent a novel therapeutic agent for RA.