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。通过胶原诱导关节炎（CIA）模型和实验性变应性脑炎（EAE）模型小鼠实验验证了其疗效。为了阐明他汀类药物对其他自身免疫性疾病的有益作用，我们用氟伐他汀对MRL-lpr/lpr小鼠、Fas缺乏的人系统性红斑狼疮（SLE）模型小鼠进行了体内治疗。方法：4 ~ 5周龄雌性MRL-lpr/lpr小鼠分为3组（n=20/组）：第16周龄时，每组灌胃生理盐水（对照，C）、氟伐他汀10mg/kg(F)或甲基强的松龙10mg/kg(P)，每周3次。通过尿蛋白、尿潜血、抗双链抗体、血清肌酐、肌酸磷酸激酶、总胆固醇水平、ifn - γ和生存率来评估疗效。结果：治疗8周后，尿蛋白（C=1.17，F=0.47）、尿隐血（C=1.44，F=0.58）、血清胆固醇（C=234.8，F=179.8）、γ干扰素（C=41.3ng/ml， F=18.7ng/ml）水平明显下降。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4个月后，氟伐他汀治疗组生存率有高于对照组的趋势，但差异无统计学意义。结论：氟伐他汀可能通过降低ifn - γ使Th1/Th2平衡向Th2方向转移，从而改善患者的尿液检查结果，甚至提高患者的生存率。

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.