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  本文關(guān)鍵詞：PMA調(diào)節(jié)免疫因子IL-2mRNA穩(wěn)定的分子機(jī)制研究　出處：《復(fù)旦大學(xué)》2010年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： T細(xì)胞 IL-2 信號轉(zhuǎn)導(dǎo) 有絲分裂原 NF90 PKC 磷酸化

【摘要】：白細(xì)胞介素2(IL-2)是維持細(xì)胞免疫功能的重要細(xì)胞因子,當(dāng)受到抗原或有絲分裂原刺激時,能被快速誘導(dǎo)出來,作為自分泌和旁分泌因子參與克隆性的T細(xì)胞擴(kuò)增,影響免疫應(yīng)答。IL-2可以在轉(zhuǎn)錄水平和轉(zhuǎn)錄后水平受到調(diào)控。IL-2mRNA3' UTR區(qū)的富集腺嘌呤尿嘧啶保守區(qū)域(AU-rich elements, AREs),介導(dǎo)了mRNA的降解,與ARE結(jié)合的蛋白(AU-binding protein, AUBP)能改變mRNA降解的速率。NF90是一個重要的調(diào)控IL-2 mRNA穩(wěn)定性的蛋白。當(dāng)T細(xì)胞激活后,NF90出核至胞質(zhì),與IL-2 mRNA的3'UTR ARE區(qū)結(jié)合并穩(wěn)定IL-2 mRNA.在前期的工作中,我們發(fā)現(xiàn)CD3/CD28共刺激后,被激活的AKT進(jìn)一步磷酸化NF90的Ser647,引起NF90出核,進(jìn)而發(fā)揮穩(wěn)定IL-2 mRNA的作用。PMA是PKC的激活劑。當(dāng)T細(xì)胞受到PMA刺激時,IL-2 mRNA豐度會立即上升,這種應(yīng)答變化除了通過IL-2的轉(zhuǎn)錄激活機(jī)制之外,是否還有IL-2 mRNA的穩(wěn)定性變化機(jī)制參與其中?如有這種可能,又是怎樣的分子調(diào)節(jié)機(jī)制呢?我們對此問題進(jìn)行了如下探討。 在本文中,我們發(fā)現(xiàn)在Jurkat T細(xì)胞中,PMA激活可引起PKCβ1磷酸化NF90的Ser647。并證明這個磷酸化反應(yīng)對于NF90應(yīng)答PMA的刺激而出核以及穩(wěn)定IL-2的mRNA是必要的。還觀察到,Jurkat T細(xì)胞在應(yīng)答PMA的刺激中,PKCβ1對NF90-Ser647的磷酸化同樣能上調(diào)IL-2的蛋白量。 根據(jù)上述的研究結(jié)果,我們提出了一條PMA穩(wěn)定IL-2 mRNA的可能分子通路。PMA刺激一方面可以通過Ca2+途徑激活NF-κB對IL-2的轉(zhuǎn)錄,另一方面也能通過激活PKCβ1進(jìn)入細(xì)胞核內(nèi)磷酸化NF90-Ser647,促使NF90出核到胞質(zhì)中,進(jìn)而穩(wěn)定IL-2 mRNA。這些新的發(fā)現(xiàn)提示T細(xì)胞在受內(nèi)源免疫因子或外源有絲分裂原等不同的刺激時,可通過不同的途徑來激活I(lǐng)L-2基因的轉(zhuǎn)錄,并穩(wěn)定1L-2mRNA,從而增加IL-2的合成與分泌,提高T細(xì)胞對內(nèi)、外源免疫刺激的應(yīng)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.

【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2010
【分類號】：R363

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