Nakayama Takashi, Hieshima Kunio, Nagakubo Daisuke, Sato Emiko, Nakayama Masahiro, Kawa Keisei, Yoshie Osamu
Department of Microbiology, Kinki University School of Medicine, Osaka-Sayama, Osaka 589-8511, Japan.
J Virol. 2004 Feb;78(4):1665-74. doi: 10.1128/jvi.78.4.1665-1674.2004.
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-1 alpha/CCL3, MIP-1 beta/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-kappa B 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-kappa B 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-kappa B 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.
趋化因子可能在与爱泼斯坦 - 巴尔病毒(EBV)相关疾病的病理生理学中发挥重要作用。在此,我们分析了EBV感染的B细胞所表达的趋化因子谱。B细胞的EBV感染诱导了TARC/CCL17和MDC/CCL22的表达,已知它们通过CCR4吸引Th2细胞和调节性T细胞,并且还上调了MIP-1α/CCL3、MIP-1β/CCL4和RANTES/CCL5的组成型表达,已知它们通过CCR5吸引Th1细胞和细胞毒性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。EBV感染或LMP1的稳定表达也在B细胞系BJAB中诱导了CCL17和CCL22。TRAF/NF-κB途径的抑制剂(BAY11-7082)和p38/ATF2途径的抑制剂(SB202190)选择性地抑制了EBV永生化B细胞和BJAB-LMP1中CCL17和CCL22的表达。一致地,使用CCL22启动子 - 报告基因构建体的瞬时转染试验表明,两个NF-κB位点和一个单一的AP-1位点参与了LMP1对CCL22启动子的激活。最后,传染性单核细胞增多症患者血清CCL22水平显著升高。总体而言,LMP1通过激活NF-κB以及可能的ATF2在EBV感染的B细胞中诱导CCL17和CCL22。吸引Th2和调节性T细胞的CCL17和CCL22的产生可能有助于EBV感染的B细胞逃避免疫监视。然而,EBV感染的B细胞同时产生CCL3、CCL4和CCL5最终可能吸引Th1细胞和细胞毒性T细胞,导致潜伏III期的EBV感染B细胞被清除,并选择潜伏基因表达有限的细胞。