SLE合并激素抵抗由于治疗困难而严重影响患者预后。我们已发现巨噬细胞游走抑制因子(MIF)可通过调控NF-κB/IκB信号通路参与SLE患者的激素抵抗发生机制，并证实MIF影响SLE患者的激素敏感性(发表于Arthritis Research & Therapy)。近来有依据表明膜联蛋白-1(annexin-1)是MIF的重要上游信号蛋白且与激素抵抗有关,此外，研究也显示MIF基因启动子区多态性可影响MIF表达。故本研究拟通过以下三方面：1. annexin-1与MIF-NF-κB/IκB调控通路的关系；2. SLE患者对激素不同应答的遗传学原因；3. MRL/lpr及MIF转基因MRL/lpr小鼠实体模拟靶向治疗的研究，以期能深入诠释SLE激素抵抗发生机制，并探讨annexin-1及MIF作为影响激素敏感性的药物靶点的可能性及挖掘MIF等位基因作为临床预测激素治疗反应的生物标志物的潜力。

Some patients with systemic lupus erythematosus (SLE) exhibit clinical resistance to glucocoticoid therapy,which constructs an obstacle to the remission of SLE.In our previous work,we have revealed that macrophage migration inhibitory factor(MIF) paly a key role in steroid sensitivity in SLE and it works through impacts on the NF-κB/IκB signaling cascade.These observations can be of significance in elucidating the underlying mechanisms behind steroid resistance. Based on the these observations,we will further explore the upstream regulatory mechanisms about MIF affecting glucocorticoid sensitivity in SLE patients.There is evidence that annexin-1 ,an upstream protein, can exert endogeneous antiinflammatory effects via regulating MIF and also mediates the antiinflammatory actions of dexamethasone.Also,the results from some recent studies showed that MIF gene promoter polymorphisms correlate with MIF expression.In our study,we will explore the role of annexin-1 in the interactions between MIF and glucocorticoid in SLE first time.We aim to find that the down-regulation of annexin-1 expression promotes the synthesis of MIF and then upregulates the activation of NF-κB/IκB signaling transduction pathway and to some extent glucocorticoid resistance.In addition,we will also investigate whether the MIF gene promoter polymorphisms correlates with glucocorticoid sensitivity in steroid-sensitive and steroid-resistant SLE patients.And, we will try some target therapies based on MRL/lpr and MRL/lpr (MIF knocking in)mice by means of anti-MIF and annexin-1 antagonist. The studies will tell us if annexin-1 and MIF can be a promising upstream target affecting glucocorticoid sensitivity and if MIF alleles can be regarded as a biomarker in evaluating the response to glucocorticoid therapy in patients with SLE.