Epstein-Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-kappa B pathway involving TNF receptor-associated factors
Epstein-Barr virus-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-kappa B pathway involving TNF receptor-associated factors
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DOI：
10.1038/sj.onc.1201258
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发表时间：
1997-06-19
期刊：
影响因子：
8
通讯作者：
Young, LS
中科院分区：
文献类型：
--
作者：
Eliopoulos, AG;Stack, M;Young, LS
转化LMP 1的EB病毒（EBV）在B细胞中的表达激活转录因子NF-κ B并通过蛋白质C-末端的两个不同结构域诱导表型变化，LMP 1的aa 187-231结构域，其对生长转化很重要，结合肿瘤坏死因子（TNF）受体相关因子（TRAF）1和TRAF 3，并且这种相互作用介导随后的信号传导事件。TRAF还与CD 40结合，TNFR家族的一个成员，其在连接后激活NF-κ B并诱导与LMP 1介导的表型变化相似的表型变化。该研究表明，癌细胞系和SV 40转化的角质形成细胞中的LMP 1表达导致诱导多效性细胞因子白细胞介素6（IL 6），这也是在CD 40连接后观察到的效果。发现LMP 1表达或CD 40连接诱导IL 6产生的机制是NF-κ B依赖性的。突变分析鉴定了LMP 1的C末端中对NF-κ B活化和IL 6分泌重要的结构域，LMP 1和CD 40共享共同的PxQxT核心TRAF结合基序，并且该序列中或邻近该序列的突变损害了LMP 1或CD 40诱导NF-κ B活化和IL 6分泌的能力，TRAF相互作用在介导这些效应中的重要性使用显性负性TRAF 2和TRAF 3突变体证实，其还鉴定了由两种NF-κ B介导的信号传导事件的差异。LMP 1的κ B激活结构域。A20是一种与TRAF 2相互作用并阻断CD 40介导的NF-κ B活性的抗凋亡蛋白，也阻断LMP 1转染的上皮细胞中NF-κ B和IL 6的分泌。这些结果表明，LMP 1以类似于CD 40连接的方式调节上皮细胞中IL 6的产生，并暗示TRAF是通过CD 40和LMP 1途径产生的信号转导中的共同介质。由于IL 6在调节上皮细胞生长中的作用先前已被提出，通过CD 4 O和LMP 1途径控制IL 6分泌可能对正常和转化的上皮细胞的生长具有影响。
Expression of the Epstein-Barr virus (EBV) transforming LMP1 in B cells activates the transcription factor NF-kappa B and induces phenotypic changes through two distinct domains in the cytoplasmic C-terminus of the protein, The aa 187-231 domain of LMP1, which is important for growth transformation, binds tumour necrosis factor (TNF) receptor associated factor (TRAF) 1 and TRAF3 and this interaction mediates subsequent signalling events, The TRAFs also associate with CD40, a member of the TNFR family, which upon ligation activates NF-kappa B and induces phenotypic changes similar to those mediated by LMP1. This study demonstrates that LMP1 expression in carcinoma cell lines and SV40-transformed keratinocytes results in induction of the pleiotropic cytokine interleukin 6 (IL6), an effect which is also observed upon CD40 Ligation. The mechanism by which either LMP1 expression or CD40 ligation induces IL6 production was found to be NF-kappa B-dependent. Mutational analysis identified domains in the C-terminus of LMP1 which are important for NF-KB activation and IL6 secretion, LMP1 and CD40 share a common PxQxT core TRAF binding motif and mutations in or adjacent to this sequence impaired the ability of LMP1 or CD40 to induce NF-kappa B activation and IL6 secretion, The importance of TRAF interactions in mediating these effects was confirmed using dominant negative TRAF2 and TRAF3 mutants which also identified differences in the signalling events mediated by the two NF-kappa B activating domains of LMP1. A20, an anti-apoptotic protein which interacts with TRAF2 and blocks CD40-mediated NF-kappa B activity, also blocked NF-kappa B and IL6 secretion in LMP1-transfected epithelial cells, These results suggest that LMP1 regulates IL6 production in epithelial cells in a manner similar to CD40 ligation and implicate TRAFs as common mediators in the transduction of signals generated via the CD40 and LMP1 pathways, As a role for IL6 in regulating epithelial cell growth has previously been suggested, the control of IL6 secretion via the CD4O and LMP1 pathways may have implications for the growth of both normal and transformed epithelial cells.