Bazedoxifene治疗SLE小鼠的疗效及对CD4^(+)T细胞亚群的影响

Efficacy of bazedoxifene in the treatment of SLE mice and regulating CD4^(+)T cell subsets

目的白细胞介素-6(IL-6)与系统性红斑狼疮疾病活动相关,是治疗系统性红斑狼疮的潜在靶点。雌激素-雌激素受体在诱发和加重SLE方面发挥一定的作用。巴多昔芬(bazedoxifene,BAZ)作为新型的第三代选择性雌激素受体调节剂,可与白细胞介素-6受体gp130 D1区域结合,拮抗白细胞介素-6的生物学作用。本研究探讨巴多昔芬治疗系统性红斑狼疮小鼠的疗效及对CD4^(+)T细胞亚群的影响。方法给予18周龄的MRL/lpr雌鼠巴多昔芬20 mg·(kg·d)^(-1)(n=6),对照组给予等量的辅料(n=6),4周后杀死小鼠,评估小鼠脾重指数(脾重/体重)、血清抗dsDNA抗体含量、24 h尿蛋白定量及肾脏病理损伤情况,流式细胞术检测脾脏CD4^(+)T细胞亚群。结果与对照组相比,巴多昔芬治疗1月显著降低系统性红斑狼疮小鼠脾重指数、24 h尿蛋白,对血清dsDNA抗体含量没有显著影响。肾脏病理进一步表明,巴多昔芬治疗显著改善系统性红斑狼疮小鼠肾小球增生性病变和肾小管间质炎性细胞浸润。巴多昔芬显著降低系统性红斑狼疮小鼠脾脏Th2细胞比例,提高Treg比例,对Th1和Th17亚群没有显著影响。结论巴多昔芬对系统性红斑狼疮小鼠和狼疮性肾炎有显著的治疗作用,并可调节Th2/Treg平衡。

Objective Interleukin(IL)-6 is related to systemic lupus erythematosus(SLE)disease activity and is a potential target for the treatment of SLE.Estrogen-estrogen receptors play a certain role in inducing and aggravating SLE.Bazedoxifene(BAZ),as a new third-generation selective estrogen receptor modulator,could bind to the IL-6 receptor gp130 D1 region and antagonize the biological effects of IL-6.This study explored the efficacy of BAZ in the treatment of SLE mice and regulating CD4^(+)T cells subsets.Methods BAZ 20 mg·(kg·d)^(-1)(n=6)was given to 18-week female MRL/lpr mice,the same amount of excipients treatment were as the control(n=6).The mice were sacrificed after 4 weeks treatment.Then the spleen weight index was evaluated and anti-dsDNA antibody content in serum and 24-hour urine protein were determined.Kidney pathological damage was further evaluated.Meanwhile,the ratio of T helper cells(Th)and regulatory T cells(Treg)in the spleen were analyzed by flow cytometry.Results Compared with the control,BAZ treatment for 4 weeks significantly reduced the spleen weight index and 24-hour urine protein,but had no significant effect on the serum dsDNA antibody content.Results of renal pathology further showed that BAZ can significantly reduce glomerular proliferative lesions and inflammatory cells infiltration in tubulointerstitium.BAZ significantly reduced the proportion of Th2 cells in the spleen of SLE mice and increased the proportion of Treg,but had no significant effect on Th1 and Th17 subgroups.Conclusion BAZ has therapeutic effects on SLE and lupus nephritis in mice,and can regulate Th2/Treg balance.