PDF(Pubmed)
Abstract：
The transcription factor Fli-1, a member of the ETS family of transcription factors, is implicated in the pathogenesis of lupus disease. Reduced Fli-1 expression in lupus mice leads to decreased renal Cxcl10 mRNA levels and renal infiltrating CXCR3+ T cells that parallels reduced renal inflammatory cell infiltration and renal damage. Inflammatory chemokine CXCL10 is critical for attracting inflammatory cells expressing the chemokine receptor CXCR3. The CXCL10/CXCR3 axis plays a role in the pathogenesis of various inflammatory diseases including lupus. Our data here demonstrate that renal CXCL10 protein levels are significantly lower in Fli-1 heterozygous MRL/lpr mice compared to wild-type MRL/lpr mice. Knockdown of Fli-1 significantly reduced CXCL10 secretion in mouse and human endothelial cells, and human mesangial cells, upon LPS or TNFα stimulation. The Fli-1 inhibitor, Camptothecin, significantly reduced CXCL10 production in human monocyte cells upon interferon stimulation. Four putative Ets binding sites in the Cxcl10 promoter showed significant enrichment for FLI-1; however, FLI-1 did not directly drive transcription from the human or mouse promoters, suggesting FLI-1 may regulate CXCL10 expression indirectly. Our results also suggest that the DNA binding domain of FLI-1 is necessary for regulation of human hCXCR3 promotor activity in human T cells and interactions with co-activators. Together, these results support a role for FLI-1 in modulating the CXCL10-CXCR3 axis by directly or indirectly regulating the expression of both genes to impact lupus disease development. Signaling pathways or drugs that reduce FLI-1 expression may offer novel approaches to lupus treatment.
摘要：
转录因子Fli-1是ETS转录因子家族的成员,与狼疮疾病的发病机理有关。狼疮小鼠中Fli-1表达的降低导致肾脏Cxcl10mRNA水平的降低和肾脏浸润CXCR3+T细胞的降低，这与肾脏炎症细胞浸润和肾脏损伤的降低平行。炎性趋化因子CXCL10对于吸引表达趋化因子受体CXCR3的炎性细胞至关重要。CXCL10/CXCR3轴在包括狼疮在内的各种炎性疾病的发病机理中起作用。我们的数据表明，与野生型MRL/lpr小鼠相比，Fli-1杂合MRL/lpr小鼠的肾CXCL10蛋白水平显着降低。敲除Fli-1显著降低小鼠和人内皮细胞的CXCL10分泌，和人类肾小球系膜细胞，在LPS或TNFα刺激时。Fli-1抑制剂,喜树碱,干扰素刺激后，人类单核细胞中CXCL10的产生显着降低。Cxcl10启动子中的四个推定Ets结合位点显示出FLI-1的显着富集；然而，FLI-1不直接驱动人或小鼠启动子的转录，提示FLI-1可能间接调控CXCL10的表达。我们的结果还表明，FLI-1的DNA结合结构域对于调节人T细胞中的人hCXCR3启动子活性以及与共激活剂的相互作用是必需的。一起,这些结果支持FLI-1通过直接或间接调节CXCL10-CXCR3轴的表达以影响狼疮疾病的发展而在调节这两个基因中发挥作用.降低FLI-1表达的信号通路或药物可能为狼疮治疗提供新的方法。
