PMA调节免疫因子IL-2mRNA稳定的分子机制研究

发布时间：2018-01-04 08:41

本文关键词：PMA调节免疫因子IL-2mRNA稳定的分子机制研究　出处：《复旦大学》2010年博士论文　论文类型：学位论文

【摘要】：白细胞介素2(IL-2)是维持细胞免疫功能的重要细胞因子,当受到抗原或有丝分裂原刺激时,能被快速诱导出来,作为自分泌和旁分泌因子参与克隆性的T细胞扩增,影响免疫应答。IL-2可以在转录水平和转录后水平受到调控。IL-2mRNA3' UTR区的富集腺嘌呤尿嘧啶保守区域(AU-rich elements, AREs),介导了mRNA的降解,与ARE结合的蛋白(AU-binding protein, AUBP)能改变mRNA降解的速率。NF90是一个重要的调控IL-2 mRNA稳定性的蛋白。当T细胞激活后,NF90出核至胞质,与IL-2 mRNA的3'UTR ARE区结合并稳定IL-2 mRNA.在前期的工作中,我们发现CD3/CD28共刺激后,被激活的AKT进一步磷酸化NF90的Ser647,引起NF90出核,进而发挥稳定IL-2 mRNA的作用。PMA是PKC的激活剂。当T细胞受到PMA刺激时,IL-2 mRNA丰度会立即上升,这种应答变化除了通过IL-2的转录激活机制之外,是否还有IL-2 mRNA的稳定性变化机制参与其中?如有这种可能,又是怎样的分子调节机制呢?我们对此问题进行了如下探讨。在本文中,我们发现在Jurkat T细胞中,PMA激活可引起PKCβ1磷酸化NF90的Ser647。并证明这个磷酸化反应对于NF90应答PMA的刺激而出核以及稳定IL-2的mRNA是必要的。还观察到,Jurkat T细胞在应答PMA的刺激中,PKCβ1对NF90-Ser647的磷酸化同样能上调IL-2的蛋白量。根据上述的研究结果,我们提出了一条PMA稳定IL-2 mRNA的可能分子通路。PMA刺激一方面可以通过Ca2+途径激活NF-κB对IL-2的转录,另一方面也能通过激活PKCβ1进入细胞核内磷酸化NF90-Ser647,促使NF90出核到胞质中,进而稳定IL-2 mRNA。这些新的发现提示T细胞在受内源免疫因子或外源有丝分裂原等不同的刺激时,可通过不同的途径来激活IL-2基因的转录,并稳定1L-2mRNA,从而增加IL-2的合成与分泌,提高T细胞对内、外源免疫刺激的应答能力。
[Abstract]:Interleukin 2 (IL-2) is an important cytokine to maintain cellular immune function, when subjected to antigen or mitogen stimulation, can be induced, as autocrine and paracrine factors involved in the clonal expansion of T cells, affect the immune response of.IL-2 can be regulated by.IL-2mRNA3'UTR enrichment of adenine uracil conservative area at the transcriptional level and post transcriptional level (AU-rich, elements, AREs) mediated the degradation of mRNA, and the ARE binding proteins (AU-binding protein, AUBP).NF90 can change the mRNA degradation rate is an important regulation of IL-2 stability of mRNA protein. When T cells were activated after NF90 from nucleus to cytoplasm mRNA, IL-2 and 3'UTR ARE and IL-2 mRNA. with stable in previous work, we found that CD3/CD28 co stimulation, activation of AKT further phosphorylation of NF90 Ser647, caused by NF90 from the nucleus, and then play IL-2 .PMA mRNA is the activator of PKC. When T cells were stimulated by PMA, IL-2 mRNA abundance will rise immediately, this response changes in transcription by IL-2 activation mechanism, whether there are changes in IL-2 mRNA stability mechanism involved? If it is possible, and molecular regulation mechanism of how we? This problem is as follows.
In this paper, we found in Jurkat T cells, PMA activation can induce PKC beta 1 phosphorylation of NF90 and Ser647. proved that the phosphorylation reaction for NF90 response to PMA stimulation and stable nuclear IL-2 mRNA is necessary. Also observed that Jurkat T cells in response to PMA stimulation, PKC beta 1 of the phosphorylation of NF90-Ser647 protein can also up-regulated the expression of IL-2.
According to the above results, we proposed a possible molecular pathway of.PMA PMA stability IL-2 mRNA hand stimulation can activate the transcription of NF- kappa B to IL-2 through the Ca2+ pathway, on the other hand can also activate PKC beta 1 into the nucleus of phosphorylated NF90-Ser647, prompting NF90 from nucleus to cytoplasm, and stable IL-2 mRNA. these new findings suggest that in T cells by endogenous immune factors or exogenous mitogens such as different stimuli, through different pathways to activate the transcription of IL-2 gene, and 1L-2mRNA, IL-2 can increase the synthesis and secretion of T cells to improve response ability, exogenous immune stimulation.

【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R363

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