Casp8p41 expression in primary T cells induces a proinflammatory response.
Casp8p41 expression in primary T cells induces a proinflammatory response.
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DOI：
10.1097/qad.0b013e3283389e90
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发表时间：
2010-06-01
期刊：
影响因子：
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通讯作者：
Badley AD
中科院分区：
文献类型：
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作者：
Taylor JA;Cummins NW;Bren GD;Rizza SA;Kolbert CP;Behrens MD;Knutson KL;Kahl JC;Asmann YW;Badley AD
HIV感染的CD4T细胞可以导致HIV蛋白酶介导的对原天冬氨酸蛋白酶8的裂解，产生一种新的HIV特异的多肽，称为Casp8p41。Casp8p41至少有两个生物学功能：通过线粒体去极化和释放细胞色素C诱导细胞死亡，以及激活核因子kappaB(NFκB)。我们先前已经证明，Casp8p41诱导的NFκB激活增强了艾滋病毒LTR的转录，从而增加了艾滋病毒的复制。在这里，我们质疑Casp8p41诱导的NFκB激活是否影响表达Casp8p41的细胞的细胞因子谱。表达Casp8p41的细胞和HIV感染的T细胞的分析我们使用微阵列分析、细胞因子定量、免疫印迹和流式细胞术来评估Casp8p41产生后宿主基因是否被转录激活。微阵列分析发现259个基因在Casp8p41表达后显著上调。此外，Casp8p41在原代CD4T细胞中的表达导致IL-2、IL-15和肿瘤坏死因子以及IL-1RA的产生增加，而在表达Casp8p41的细胞中粒-巨噬细胞集落刺激因子和干扰素-γ的水平降低。细胞内流式细胞术证实了Casp8p41与HIV感染细胞中升高的肿瘤坏死因子之间的共同关系。这些数据表明，Casp8p41在HIV感染的CD4T细胞中的表达除了促进细胞凋亡和增强HIV复制外，还促进了促炎细胞因子环境，这是未经治疗的HIV感染的特征。
HIV infection of CD4 T cells can lead to HIV protease-mediated cleavage of procaspase 8 generating a novel, HIV-specific peptide called Casp8p41. Casp8p41 has at least two biologic functions: induction of cell death via mitochondrial depolarization and release of cytochrome C, as well as activation of nuclear factor kappa B (NFκB). We have previously shown that Casp8p41-induced NFκB activation enhances HIV LTR transcription and consequently increases HIV replication. Herein, we questioned whether Casp8p41-induced NFκB activation impacts the cytokine profile of cells expressing Casp8p41. Analysis of cells expressing Casp8p41 and HIV-infected T cells. We assessed whether host genes are transcriptionally activated following Casp8p41 production, using microarray analysis, cytokine quantification, followed by western blot and flow cytometry. Microarray analysis identified 259 genes significantly upregulated following expression of Casp8p41. Furthermore, Casp8p41 expression in primary CD4 T cells results in increased production of interleukin (IL)-2, IL-15 and tumor necrosis factor (TNF), as well as IL-1RA; whereas levels of granulocyte macrophage colony-stimulating factor and interferon (IFN)-γ were reduced in the Casp8p41 expressing cells. Intra-cellular flow cytometry confirmed the co-association of Casp8p41 with elevated TNF in HIV-infected cells. These data indicate that the expression of Casp8p41 in HIV-infected CD4 T cells in addition to promoting apoptosis and enhancing HIV replication also promotes a proinflammatory cytokine milieu, which is characteristic of untreated HIV infection.