Inhibition of p38 MAP kinase pathway induces apoptosis and prevents Epstein Barr virus reactivation in Raji cells exposed to lytic cycle inducing compounds.
Inhibition of p38 MAP kinase pathway induces apoptosis and prevents Epstein Barr virus reactivation in Raji cells exposed to lytic cycle inducing compounds.
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DOI：
10.1186/1476-4598-8-18
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发表时间：
2009-03-09
期刊：
影响因子：
37.3
通讯作者：
Mattia E
中科院分区：
文献类型：
--
作者：
Matusali G;Arena G;De Leo A;Di Renzo L;Mattia E
EBV裂解周期激活剂，如佛波醇酯、抗免疫球蛋白、转化生长因子β（TGFβ）、丁酸钠，在EBV阴性但不在EBV阳性伯基特淋巴瘤（BL）细胞中诱导凋亡。要调查的分子机制，使EBV感染的细胞得到保护，我们研究了病毒和细胞抗凋亡蛋白的表达，以及在BL-衍生的Raji细胞暴露于裂解周期诱导剂的信号转导通路的激活。我们的数据显示，在EBV活化后，潜伏膜蛋白1（LMP 1）和细胞抗凋亡蛋白MCL-1和BCL-2迅速上调，并且Raji细胞即使同时暴露于P（BU）2、丁酸钠和TGFβ时也保持存活。我们在这里报告，抑制p38通路，在EBV激活，导致细胞凋亡的三倍增加，并在很大程度上阻止裂解基因的表达。这些发现表明，在EBV感染的潜伏期到裂解期的转换过程中，p38 MAPK磷酸化在保护宿主细胞免于凋亡以及诱导病毒再活化方面起着关键作用。由于Raji细胞是有缺陷的晚期抗原表达，我们推测，在EBV裂解周期的早期阶段LMP 1基因表达的增加可能有助于EBV阳性细胞的存活。
EBV lytic cycle activators, such as phorbol esters, anti-immunoglobulin, transforming growth factor β (TGFβ), sodium butyrate, induce apoptosis in EBV-negative but not in EBV-positive Burkitt's lymphoma (BL) cells. To investigate the molecular mechanisms allowing EBV-infected cells to be protected, we examined the expression of viral and cellular antiapoptotic proteins as well as the activation of signal transduction pathways in BL-derived Raji cells exposed to lytic cycle inducing agents. Our data show that, following EBV activation, the latent membrane protein 1 (LMP1) and the cellular anti-apoptotic proteins MCL-1 and BCL-2 were quickly up-regulated and that Raji cells remained viable even when exposed simultaneously to P(BU)2, sodium butyrate and TGFβ. We report here that inhibition of p38 pathway, during EBV activation, led to a three fold increment of apoptosis and largely prevented lytic gene expression. These findings indicate that, during the switch from the latent to the lytic phase of EBV infection, p38 MAPK phosphorylation plays a key role both for protecting the host cells from apoptosis as well as for inducing viral reactivation. Because Raji cells are defective for late antigens expression, we hypothesize that the increment of LMP1 gene expression in the early phases of EBV lytic cycle might contribute to the survival of the EBV-positive cells.
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影响因子：
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