Selective induction of Th2-attracting chemokines CCL17 and CCL22 in human B cells by latent membrane protein 1 of Epstein-Barr virus
Selective induction of Th2-attracting chemokines CCL17 and CCL22 in human B cells by latent membrane protein 1 of Epstein-Barr virus
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DOI：
10.1128/jvi.78.4.1665-1674.2004
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发表时间：
2004-02-01
影响因子：
5.4
通讯作者：
Yoshie, O
中科院分区：
文献类型：
--
作者：
Nakayama, T;Hieshima, K;Yoshie, O
趋化因子可能在EB病毒相关疾病的病理生理学中发挥重要作用。在这里，我们分析了EB病毒感染的B细胞表达的趋化因子的谱系。EBV感染B细胞诱导TARC/CCL17和MDC/CCL22的表达，MIP-1α/CCL3、MIP-1β/CCL4和RANTES/CCL5的表达上调，MIP-1α/CCL3、MIP-1β/CCL4和RANTES/CCL5通过CCR5吸引Th1细胞和细胞毒T细胞。因此，EBV永生化的B细胞大量分泌这些趋化因子，尤其是CCL3、CCL4和CCL22。EB病毒感染或LMP1的稳定表达也可诱导B细胞系BJAB产生CCL17和CCL22。TRAF/NF-kappaB通路的抑制剂(BAY11-7082)和p38/ATF2通路的抑制剂(SB202190)选择性地抑制EBV永生化B细胞和BJAB-LMP1中CCL17和CCL22的表达。使用CCL22启动子-报告构建的瞬时转染分析表明，LMP1激活CCL22启动子的过程中涉及两个NF-kappaB位点和一个AP-1位点。最后，传染性单核细胞增多症患者血清CCL22水平显著升高。总的来说，LMP1通过激活NF-kappaB和可能的ATF2诱导EB病毒感染的B细胞中的CCL17和CCL22。CCL17和CCL22的产生吸引了Th2和调节性T细胞，可能有助于EBV感染的B细胞逃避Th1细胞的免疫监视。然而，EB病毒感染的B细胞同时产生CCL3、CCL4和CCL5可能最终吸引Th1细胞和细胞毒性T细胞，导致在潜伏期III消除EBV感染的B细胞，并选择潜伏基因表达有限的B细胞。
Chemokines are likely to play important roles in the pathophysiology of diseases associated with Epstein-Barr virus (EBV). Here, we have analyzed the repertoire of chemokines expressed by EBV-infected B cells. EBV infection of B cells induced expression of TARC/CCL17 and MDC/CCL22, which are known to attract Th2 cells and regulatory T cells via CCR4, and also upregulated constitutive expression of MIP-1alpha/CCL3, MIP-1beta/CCL4, and RANTES/CCL5, which are known to attract Th1 cells and cytotoxic T cells via CCR5. Accordingly, EBV-immortalized B cells secreted these chemokines, especially CCL3, CCL4, and CCL22, in large quantities. EBV infection or stable expression of LMP1 also induced CCL17 and CCL22 in a B-cell line, BJAB. The inhibitors of the TRAF/NF-kappaB pathway (BAY11-7082) and the p38/ATF2 pathway (SB202190) selectively suppressed the expression of CCL17 and CCL22 in EBV-immortalized B cells and BJAB-LMP1. Consistently, transient-transfection assays using CCL22 promoter-reporter constructs demonstrated that two NF-kappaB sites and a single AP-1 site were involved in the activation of the CCL22 promoter by LMP1. Finally, serum CCL22 levels were significantly elevated in infectious mononucleosis. Collectively, LMP1 induces CCL17 and CCL22 in EBV-infected B cells via activation of NF-kappaB and probably ATF2. Production of CCL17 and CCL22, which attract Th2 and regulatory T cells, may help EBV-infected B cells evade immune surveillance by Th1 cells. However, the concomitant production of CCL3, CCL4, and CCL5 by EBV-infected B cells may eventually attract Th1 cells and cytotoxic T cells, leading to elimination of EBV-infected B cells at latency III and to selection of those with limited expression of latent genes.