TACI-Ig对MRL/lpr小鼠的治疗作用及其对小鼠肾组织JAK1-STAT1信号通路的影响

目的研究TACI-Ig对MRL/lpr小鼠的治疗作用以及TACI-Ig对狼疮性肾炎肾组织JAK1-STAT1信号通路活化的影响。方法将MRL/lpr红斑狼疮转基因小鼠随机分成6组,即模型组、TACI-Ig 3个剂量治疗组(3.75、7.5、15 mg.kg-1)组、强的松阳性对照组和IgG-Fc阴性对照组,另选用BALB/c小鼠作为正常对照组。除强的松组每日灌胃给药外,其余各组隔日皮下注射给药,共计8周,模型组和正常组给予生理盐水。观察TACI-Ig对MRL/lpr小鼠一般体征、损伤指数的影响,目测半定量尿蛋白试纸法检测动物的尿蛋白变化,HE染色法观察肾组织病理学改变情况,全自动生化分析仪检测血清中肌酐和尿素氮的水平,ELISA法检测血清中BLyS、IL-10和IFN-γ的水平,免疫组化法检测肾脏磷酸化的JAK1和STAT1的表达分布情况。结果 TACI-Ig(7.5、15mg.kg-1)皮下注射给药8周可明显降低模型小鼠的尿蛋白水平和损伤指数;有效改善肾小球系膜细胞增生和肾小球纤维化,明显减轻炎性细胞浸润;TACI-Ig给药可明显降低小鼠血清中的肌酐和尿素氮水平以及血清中BLyS、IL-10、IFN-γ等细胞因子水平。免疫组化结果显示模型组小鼠的肾脏磷酸化的JAK1和STAT1蛋白的表达明显升高,在肾小球、肾间质中呈强阳性表达,TACI-Ig给药后可使其表达明显降低。结论 TACI-Ig可明显改善MRL/lpr小鼠红斑狼疮样的临床表现和肾脏病理特征,降低血清中细胞因子和肾组织中磷酸化JAK1、STAT1蛋白的表达水平,这可能是TACI-Ig治疗狼疮性肾炎的机制之一。

Effects of TACI-Ig on MRL/lpr mice and activation of JAK1-STAT1 signaling pathway in lupus nephritis

Aim To study the effect of TACI-Ig on MRL/lpr mice and activation of JAK1-STAT1 signaling pathway in lupus nephritis.Methods MRL/lpr mice were randomly divided into 6 groups,mice in group 1 were given normal saline as model group,mice in the other five groups were given TACI-Ig(3.75,7.5,15 mg·kg-1),IgG-Fc(7.5 mg·kg-1,negative control),prednisone(5 mg·kg-1,positive control) respectively,continuously for 8 weeks.Normal control(BALB/c) group was given normal saline,and all groups were treated subcutaneously once every other day except prednisone group(intragastrically once a day).The general signs and damage index of MRL/lpr mice were observed after TACI-Ig treatment.Proteinuria of mice was detected by the demi-quantitate al-bustix.The sections of kidney tissues for pathological analysis were stained with HE.The serum levels of BUN,Cre and BLyS,IL-10,IFN-γ were determined by automatic biochemistry analyzer and ELISA kits,respectively.The expression of phosphorylated JAK1 and STAT1 in renal tissue was detected by immunohistochemical techniques.Results TACI-Ig(7.5,15 mg·kg-1) could significantly reduce the levels of proteinuria and damage index after 8 weeks.Mesangial cell hyperplasia,glomerular fibrosis and inflammatory cell infiltration were alleviated effectively.The serum levels of BUN,Cre,BLyS,IL-10 and IFN-γ were remarkably decreased too.Moreover,immunohistochemical results showed the protein expression of phosphorylated JAK1 and STAT1 in renal tissue was obviously increased in model mice,especially in glomerular and renal interstitium,while it decreased significantly by TACI-Ig administration.Conclusions TACI-Ig has a beneficial effect on murine SLE by improving the clinical manifestations and renal pathological features of MRL/lpr mice,decreasing the levels of cytokines in serum and phosphorylation of JAK1 and STAT1 in renal tissue,which might be one of the mechanisms of TACI-Ig treatment for lupus nephritis.