胶质瘤环氧化酶-2抑制剂塞来昔布对肿瘤微环境及生物学行为的影响

Effect of inhibiting cyclooxygenase-2 expression on glioma immune microenvironment and biological behavior

目的 探讨选择性环氧化酶-2（cyclooxygenase-2,COX-2）抑制剂塞来昔布（celecoxib）对大鼠脑胶质瘤免疫微环境及生物学行为的影响.方法 建立大鼠脑胶质瘤模型,观察celecoxib治疗后肿瘤大小及大鼠生存期；免疫组化法检测肿瘤组织COX-2、转化生长因子-β（transforming growth factor-beta,TGF-β）、血管内皮生长因子（vascular endothelial growth factor,VEGF）蛋白表达；流式细胞术检测肿瘤微环境CD4＋CD25＋T细胞亚群数量；酶联免疫法（ELISA）检测大鼠血清中前列环素E2（Prostaglandin E2,PGE2）、白介素-l0（IL-l0）、白介素-12（IL-12）分泌水平.结果 Celecoxib治疗组肿瘤体积明显小于对照组[（103.67±5.54） mm3,（151.60±8.34） mm3,P＜0.01],并可延长大鼠生存期[（42.87± 1.72）d,（26.13± 1.53）d,P＜0.01],肿瘤组织中COX-2、VEGF及TGF-β蛋白的表达均出现下调,其肿瘤微环境中CD4＋CD25＋T细胞亚群比例明显降低（5.32％,7.84％,P＜0.05）.血清中PGE2与IL-10水平明显下降[（223.66±33.79）pg/ml,（344.15±41.09） pg/ml,（98.69± 10.99） pg/ml,（133.37± 13.15） pg/ml,P＜0.01],而IL-12分泌明显增多[（237.20±37.31） pg/ml,（117.90±19.20） pg/ml,P＜0.01].结论 Celecoxib可通过多种途径改善肿瘤局部免疫微环境,从而改变肿瘤的生物学行为,延缓肿瘤发展,并为肿瘤治疗提供良好的基础环境.

Objective To investigate the effect of celecoxib,a selective inhibitor of cyclooxygenase-2 （COX-2）,on glioma immune microenvironment and biological action in rat.Methods After treated with celecoxib,tumor volume and survive time were observed in a rat glioma model.COX-2,transforming growth factor-beta （TGF-β） and vascular endothelial growth factor（VEGF） expression in tumor tissue were detected using immunehistory and CD4 ＋ CD25 ＋ T cells was detected by flowcytometry.By using enzyme-linked immunosorbent assay （ELISA）,the production of prostaglandin（PGE2）,interlukin 10（IL-10） and interlukin 12（IL-12） were detected in rat serum.Results Tumor volume decreased after treated with celecoxib （（103.67±5.54） mm3,（151.60±8.34）mm3,P＜0.01） and survive time of animals were prolonged （（42.87±1.72） d,（26.13±1.53）d,P＜0.01）.Expression of COX-2,TGF-β and VEGF in tumor tissue was down regulated after treated with celecoxib and number of CD4＋CD25 ＋ T cells were decreased （5.32％,7.84％,P＜ 0.05）.PGE2,IL-10 production in serum was obviously decreased by treatment of celecoxib （（223.66±33.79） pg/ml,（344.15±41.09） pg/ml,（98.69± 10.99） pg/ml,（133.37± 13.15） pg/ml,P＜0.01） while the production of IL-12 was increased （（237.20±37.31） pg/ml,（117.90±19.20） pg/ml,P＜0.01）.Conclusion Celecoxib may improve the status of immunosuppression of rat glioma by several pass ways and modify tumor biological action.Celecoxib may give a good microenvironment for immunotherapy of gliomas.