Cooperative interaction of C/EBPβ and Tat modulates MCP-1 gene transcription in astrocytes
Cooperative interaction of C/EBPβ and Tat modulates MCP-1 gene transcription in astrocytes
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DOI：
10.1016/j.jneuroim.2004.11.009
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发表时间：
2005-03-01
影响因子：
3.3
通讯作者：
Amini, S
中科院分区：
文献类型：
--
作者：
Abraham, S;Sweet, T;Amini, S
趋化蛋白-1(MCP-1)是最强的单核细胞趋化因子之一，在AIDS痴呆的发病过程中其水平升高。早期的研究表明，HIV-1Tat蛋白能够诱导星形细胞中MCP-1启动子的转录。此外，转化生长因子β-1信号通路通过其调节蛋白Smads调节MCP-1的TAT激活。在这里，我们证明了C/EBPβ，其活性在病毒感染过程中被各种细胞因子增强，可以刺激基础和TAT介导的人星形细胞MCP-1的转录。使用启动子缺失突变体的结果表明，在MCP-1启动子的-200到+1之间分布着多个C/EBPβ结合位点，这在观察到的活性中具有重要意义。DNA结合研究结果表明，C/EBPβ与其DNA基序的相互作用被C/EBPβ同源蛋白CHOP所减弱，CHOP具有抑制C/EBPβ对MCP-1转录的刺激作用。TAT具有与C/EBPβ相互作用的能力，可减轻CHOP的负面影响，恢复C/EBPβ与DNA的相互作用。此外，SMAD3及其C末端调控基序MH2与C/EBPβ相互作用，调节其在MCP-1启动子上的DNA结合和转录活性。我们的结果表明，Smad3和MH2的存在严重影响了C/EBPβ和TAT的物理和功能相互作用。总之，这些观察确认C/EBPβ是TAT在刺激星形胶质细胞MCP-1转录方面的新合作伙伴，并表明几种细胞因子和免疫调节剂下游调控蛋白之间的微妙平衡可以决定包括MCP-1在内的趋车剂的表达水平。因此，TAT对C/EBPβ和Smads等调控蛋白的不适当表达和功能可能诱导星形胶质细胞产生MCP-1，并通过刺激中枢炎症反应参与艾滋病的神经发病。(C)2004爱思唯尔B.V.保留所有权利。
The chemoattractant protein 1 (MCP-1) is one of the most potent monocyte chemoattractants whose level is elevated during the course of AIDS dementia. Earlier studies showed that HIV-1 Tat protein is able to induce transcription of the MCP-1 promoter in astrocytic cells. Furthermore, the TGF beta-1 signaling pathway through its regulatory proteins, Smads, modulates Tat activation of MCP-1. Here, we demonstrate that C/EBP beta, whose activity is enhanced by a variety of cytokines during the course of viral infection, can stimulate basal- and Tat-mediated transcription of MCP-1 in human astrocytic cells. Results using promoter deletion mutants suggested the importance of multiple C/EBP beta binding sites scattered within -200 to +1 of the MCP-1 promoter in the observed activity. Results from DNA binding studies have shown that the interaction of C/EBP beta with its DNA motif is diminished by the C/EBP beta homologous protein, CHOP, which possesses the ability to suppress the stimulatory effect of C/EBP beta on MCP-1 transcription. Tat, which possesses the ability to interact with C/EBP beta alleviates the negative effect of CHOP and restores C/EBP beta interaction with the DNA. Furthermore, Smad3 and its C-terminal regulatory motif, MH2, interact with C/EBP beta and modulate its DNA binding and transcriptional activity on the MCP-1 promoter. Our results show that the physical and functional interactions of C/EBP beta and Tat are severely affected by the presence of Smad3 and MH2. Altogether, these observations identify C/EBP beta as a new partner for Tat in stimulating MCP-1 transcription in astrocytes and suggest that the delicate balance among the downstream regulatory proteins of several cytokines and immunomodulators can dictate the level of expression of chernoattractants, including MCP-1. Hence, inappropriate expression and function of regulatory proteins such as C/EBP beta and Smads by Tat may induce MCP-1 production in astrocytes and contribute to the neuropathogenesis of AIDS through stimulation of inflammation in the CNS. (c) 2004 Elsevier B.V. All rights reserved.