噻唑烷二酮类药物抑制白介素1β和干扰素γ诱导的胰岛β细胞凋亡  

Inhibitory effects of thiazolidinedione upon cytokine-induced apoptosis in pancreatic β-cell line

作　　者：王安平[1] 李霞[1] 刘碧莲[1] 郑瑛[1] 郑超[1] 林健[1] 黄干[1] 颜湘[1] 彭健[1] 周智广[1] 

机构地区：[1]中南大学湘雅二医院代谢内分泌研究所糖尿病中心代谢综合征研究中心,长沙410011

出　　处：《中华医学杂志》2009年第28期1989-1993,共5页National Medical Journal of China

基　　金：国家自然科学基金（30600298;30670991）;国家高技术研究发展计划基金（2006AA02A409）湖南省自然科学基金（06JJ2086;08JJ4007）

摘　　要：目的观察噻唑烷二酮类药物（TZD）抑制白介素1β（IL-1β）和干扰素γ（IFN-γ）诱导胰岛β细胞凋亡的作用及对胰岛素分泌功能的影响，探讨其可能的作用机制。方法体外培养小鼠胰岛素瘤细胞（NIT-1）至指数增长期，根据干预方案进行分组：正常细胞组、IL-1β／IFN-γ组、罗格列酮（RSG）或吡格列酮（PIG）＋IL-1β/IFN-γ组、RSG或PIG＋IL-1β／IFN-γ＋GW9662组。采用Hoechst33342染色观察细胞凋亡形态变化、膜联蛋白V-FITC／PI检测凋亡率、ELISA检测胰岛素分泌，观察RSG和PIG对IL-1β和IFN-γ损伤B细胞的保护作用。结果RSG或PIG＋IL-1β／IFN-γ组凋亡率明显降低（14．0％、16．7％），与IL-1β／IFN-γ组比较差异有统计学意义（51．3％，P〈0．01）；RSG或PIG＋IL-1β和IFN-γ＋GW9662组凋亡率明显升高（41．4％、44．7％），与RSG或PIG＋IL-1β／IFN-γ组比较差异有统计学意义（P〈0．01）；同样，RSG或PIG＋IL-1β／IFN-γ组葡萄糖刺激胰岛素分泌能力（GSIS）明显恢复[（6．8±0．7）ng／ml、（5．9±0．9）ng／ml]，与IL-1β／IFN-γ组（3．6±0．5ng／ml）比较差异有统计学意义（P〈0．01）；RSG或PIG＋IL-1B和IFN-γ＋GW9662组GSIS明显降低[（3．9±0．4）ng/ml、（3．6±0．3）ng／ml]，与RSG或PIG＋IL-1β／IFN-γ组比较差异有统计学意义（P〈0．01）。结论TZD可以抑制细胞因子诱导的胰岛β细胞凋亡和恢复β细胞的胰岛素分泌功能，其机制可能与抑制半胱氨酸水解酶-3的活性有关。Objective To investigate the protective effects and potential mechanisms of TZD upon pancreatic β-cells. Methods Apoptosis was induced in vitro by interleukin-1β （IL-1β） and interferon-γ （IFN-γ）. After treatment with rosiglitazone （RSG）/ pioglitazone （PIG） at the final concentrations of 1 μmol/L, 10 μmol/L, 20 μmol/L respectively, the apoptotic rate of NIT-γ cells was determined by Hoechest33342 staining and Annexin V-FITC/PI flow cytometry respectively. Caspase-3 specific activity of NIT-1 cells was determined by Caspase-3 assay and insulin secretion measured by ELISA. Results After treatment of different concentrations of RSG/PIG, the apoptotic rate of NIT-1 cells decreased to 29. 3%, 14. 0%, 28.1% and 27.4%, 16. 7%, 23.5% respectively. There were significant differences in apoptotic rate between the RSG/PIG treatment group and IL-1 β/IFN-γ group （P 〈0. 01 ）. After treatment with RSG/ PIG, glucose-stimulated insulin secretion （GSIS） of NIT-1 cells recovered in different degrees [ （6.8 ± 0. 7）ng/ml, （5.9±0. 9）ng/ml,P 〈0.01 ]. There were significant differences in GSIS between the RSG/ PIG treatment group and IL-1β/IFN-γ group （P 〈 0. 01 ）. Moreover, most of the protective effects of TZD upon pancreatic β-cells could be blocked by a PPAR-γ inhibitor, GW9662. Conclusion TZD might protect pancreatic β-cells directly via inhibiting cytokine-induced apoptosis and recovering insulin secretion. And the mechanism may be correlated with the down-regulation of caspase-3 activity.

关 键 词：胰岛素分泌细胞 细胞凋亡 噻唑烷二酮 

分 类 号：R686[医药卫生—骨科学]