Fli-1 controls transcription from the MCP-1 gene promoter, which may provide a novel mechanism for chemokine and cytokine activation.
Fli-1 controls transcription from the MCP-1 gene promoter, which may provide a novel mechanism for chemokine and cytokine activation.
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DOI：
10.1016/j.molimm.2014.07.013
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发表时间：
2015-02
影响因子：
3.6
通讯作者：
Zhang XK
中科院分区：
文献类型：
--
作者：
Lennard Richard ML;Nowling TK;Brandon D;Watson DK;Zhang XK
促炎细胞因子和趋化因子的调节是先天免疫应答的主要作用。MCP-1是一种趋化因子，可以将免疫细胞募集到炎症部位。Fli-1转录因子杂合敲除小鼠的原代肾内皮细胞中MCP-1的表达降低Fli-1是转录因子Ets家族的成员，其在包括果蝇、非洲爪蟾、小鼠和人类在内的多种生物中进化上保守。Ets家族成员通过共有序列GGAA/T或Ets结合位点（EBS）结合DNA。通过ChIP测定，Fli-1结合内源性MCP-1启动子内的EBS。在这项研究中，瞬时转染试验表明，Fli-1基因积极促进MCP-1基因启动子的转录，并呈剂量依赖性。Fli-1的DNA结合结构域的突变表明，Fli-1通过结合启动子直接激活MCP-1的转录，以及可能通过与其他转录因子的相互作用间接激活MCP-1的转录。另一种Ets转录因子Ets-1也进行了测试，但未能促进转录。虽然Ets-1不能独立驱动转录，但在Ets-1和Fli-1之间观察到MCP-1启动子的弱协同激活。此外，发现Fli-1和NFκB家族成员p65相互作用，协同激活MCP-1启动子的转录，而Sp1和p50抑制这种相互作用。缺失研究表明，远端和近端MCP-1启动子中的EBSs对于MCP-1启动子激活Fli-1至关重要。总之，这些结果表明Fli-1是促炎趋化因子MCP-1的一种新型调节因子，其与其他转录因子相互作用以形成用于激活MCP-1和介导炎症反应的复杂转录机制。
Regulation of proinflammatory cytokines and chemokines is a primary role of the innate immune response. MCP-1 is a chemokine that recruits immune cells to sites of inflammation. Expression of MCP-1 is reduced in primary kidney endothelial cells from mice with a heterozygous knockout of the Fli-1 transcription factor. Fli-1 is a member of the Ets family of transcription factors, which are evolutionarily conserved across several organisms including Drosophilla, Xenopus, mouse and human. Ets family members bind DNA through a consensus sequence GGAA/T, or Ets binding site (EBS). Fli-1 binds to EBSs within the endogenous MCP-1 promoter by ChIP assay. In this study, transient transfection assays indicate that the Fli-1 gene actively promotes transcription from the MCP-1 gene promoter in a dose-dependent manner. Mutation of the DNA binding domain of Fli-1 demonstrated that Fli-1 activates transcription of MCP-1 both directly, by binding to the promoter, and indirectly, likely through interactions with other transcription factors. Another Ets transcription factor, Ets-1, was also tested, but failed to promote transcription. While Ets-1 failed to drive transcription independently, a weak synergistic activation of the MCP-1 promoter was observed between Ets-1 and Fli-1. In addition, Fli-1 and the NFκB family member p65 were found to interact synergistically to activate transcription from the MCP-1 promoter, while Sp1 and p50 inhibit this interaction. Deletion studies identified that EBSs in the distal and proximal MCP-1 promoter are critical for Fli-1 activation from the MCP-1 promoter. Together, these results demonstrate that Fli-1 is a novel regulator of the proinflammatory chemokine MCP-1, that interacts with other transcription factors to form a complex transcriptional mechanism for the activation of MCP-1 and mediation of the inflammatory response.
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