Analysis on Mechanism of Immunomodulatory Activity Through Apoptosis Induced by Statins

目的：羟甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类）具有抗炎和免疫调节作用。用胶原诱导的关节炎（CIA）和实验性变态反应性脑炎（EAE）小鼠模型证实其疗效。为了探讨他汀类药物对其他自身免疫性疾病的治疗作用，本研究采用氟伐他汀对Fas缺陷型人系统性红斑狼疮（SLE）模型小鼠MRL lpr/lpr小鼠进行体内治疗（n=20/组）：16周时，各组分别腹腔注射生理盐水（对照组，C）、氟伐他汀10 mg/kg（F）、甲泼尼龙10 mg/kg（P），每周3次。通过尿蛋白、尿潜血、抗双链抗体、血肌酐、肌酸磷酸激酶、总胆固醇、IFN-γ、生存率等指标评价疗效。治疗后8周，尿蛋白（C= 1.17，F =0.47）、尿潜血（C= 1.44，F =0.58）、血清胆固醇（C= 234.8，F =179.8）、干扰素γ（C=41.3ng/ml，F=18.7ng/ml）。氟伐他汀治疗组较对照组降低。未观察到肌酸磷酸激酶升高。治疗后4个月，虽然没有统计学意义，但有一种趋势，即氟伐他汀治疗组显示出更好的生存率比control group.Conclusion：有可能氟伐他汀通过降低IFN-γ，使Th 1/Th 2平衡向Th 2方向移动，从而改善他们的尿液检查结果，甚至他们的生存率。

Objective : Hydroxy-Methylglutaryl Coenzyme A(HMG-CoA) reductase inhibitors (statins) possesses anti-inflammatory and immunomodulatory effects. Its efficacy was demonstrated by in vivo model of collagen induced arthritis(CIA), and experimental allergic encephalitis(EAE) model mouse. To elucidate beneficial effects of statins on another autoimmune diseases, we conducted an in vivo treatment of MRL-lpr/lpr mouse, Fas deficient human Systemic lupus Erythematosus(SLE) model mouse by Fluvastatin.Methods : female MRL-lpr/lpr mice age between 4-5weeks were devided into 3 groups(n=20/group) : On 16 weeks, each group was administered intraperitonially with saline(control, C), Fluvastatin 10mg/kg(F), or methylprednisolone 10mg/kg(P) 3 times a week. Effects were evaluated by urine proteins, urine occult blood, anti-double strand antibody, serum creatinine, creatine phosphokinase, total cholesterol level, IFN-gamma, and survival rate.Result s: Eight weeks after treetment, Urinary proteins(C=1.17,F=0.47), urine occult blood(C=1.44,F=0.58), serum cholesterol level(C=234.8,F=179.8), and interferon gamma (C=41.3ng/ml, F=18.7ng/ml). were decreased in Fluvastatin treated group than in control group. Elevation of creatine phosphokinase was not observed. Four months after treatment, although it was not statistically significant, there was a tendency that Fluvastatin treated group showed a better survival rate than control group.Conclusion : There is a possibility that fluvastatin shifts Th1/Th2 balance towards Th2 by decreasing IFN-gamma, thereby improves their urinary findings, and even their survival rate.