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Regulation of the mouse gene encoding TAFI by TNFα: Role of NFκB binding site

机译：TNFα对编码TAFI的小鼠基因的调控：NFκB结合位点的作用

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摘要

Thrombin-activable fibrinolysis inhibitor (TAFI) is a plasma pro-carboxypeptidase, encoded by the gene CPB2, with roles in both inhibition of fibrinolysis and inflammation. In mice, plasma TAFI levels and hepatic CPB2 mRNA expression were found to increase within 24. h after intra-peritoneal lipopolysaccharide (LPS) injection. On the other hand, plasma TAFI in humans decrease in experimental endotoxemia and sepsis and we have previously demonstrated that CPB2 mRNA abundance in human hepatoma cells is decreased by inflammatory cytokines. Here, we have evaluated the effects of TNFα on mouse CPB2 expression. Treatment of primary mouse hepatocytes or the mouse hepatic cell line FL83B with TNFα for 12-48. h resulted in increases in CPB2 mRNA abundance of up to 2-fold; mouse TAFI protein levels secreted from FL83B cells increased 2.7-fold after 48. h treatment with TNFα. When FL83B cells were transfected with reporter plasmids containing the mouse CPB2 5'-flanking region, treatment with TNFα for 24 and 48. h resulted in a 1.5-fold increased mouse CPB2 promoter activity. Mutation of a putative NFκB site not conserved in the human gene ablated the increased promoter activity observed following TNFα treatment. This site binds NFκB as assessed by gel mobility shift assays, and TNFα treatment increases the translocation of NFκB from the cytoplasm to the nucleus of mouse hepatocytes. These results demonstrate that the unique NFκB site in the mouse CPB2 promoter is functional and mediates the upregulation of mouse CPB2 expression by TNFα via increase in NFκB translocation to the nucleus.
机译：凝血酶激活的纤维蛋白溶解抑制剂（TAFI）是一种血浆前羧肽酶，由基因CPB2编码，在抑制纤维蛋白溶解和炎症中均起作用。在小鼠中，发现腹膜内注射脂多糖（LPS）后24小时内血浆TAFI水平和肝CPB2 mRNA表达增加。另一方面，人类血浆TAFI在实验性内毒素血症和败血症中减少，并且我们先前已经证明，人类肝癌细胞中CPB2 mRNA的丰度通过炎性细胞因子而降低。在这里，我们评估了TNFα对小鼠CPB2表达的影响。用TNFα治疗原代小鼠肝细胞或小鼠肝细胞系FL83B，持续12-48。 h导致CPB2 mRNA丰度增加多达2倍;用TNFα处理48小时后，FL83B细胞分泌的小鼠TAFI蛋白水平增加了2.7倍。用含有小鼠CPB2 5'侧翼区的报道质粒转染FL83B细胞时，用TNFα处理24和48小时，导致小鼠CPB2启动子活性提高了1.5倍。人基因中不保守的推测的NFκB位点的突变消除了TNFα治疗后观察到的启动子活性的增加。如通过凝胶迁移率变动分析所评估，该位点结合NFκB，并且TNFα处理增加了NFκB从小鼠肝细胞的细胞质到细胞核的转运。这些结果表明，小鼠CPB2启动子中独特的NFκB位点具有功能，并通过增加NFκB易位至细胞核介导了TNFα对小鼠CPB2表达的上调。

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