探討EB病毒對細胞激素介白質13表現之調控機制

Abstract

EB病毒感染會影響宿主細胞中細胞激素的表現，進而改變了宿主細胞的命運。過去，細胞激素介白質13 曾在EB病毒相關的何杰金氏淋巴癌切片檢體中被測出；且在自然殺手細胞型慢性活化EB病毒感染的病人血清中，介白質13的量也明顯的增加；然而介白質13在EB病毒相關的疾病中所扮演的角色及生理意義則仍未被探討過，而其表現又是如何被EB病毒所調控也仍是個未知的機制。利用細胞激素抗體陣列分析，我們發現EB病毒感染B細胞之後，B細胞中介白質13的表現量會上升。更進一步的研究發現，EB病毒的溶裂期蛋白質Zta可以促進介白質13的表現量增加；而Zta誘發介白質13表現的分子機制則是透過Zta直接結合在介白質13的啟動子，進而轉活化介白質13的表現。此外，EB病毒所感染的B細胞以及EB病毒所轉染的淋巴母細胞株的生長均會受到介白質13中和抗體的抑制，顯示介白質13對這些細胞生長的重要性。根據上述的實驗結果，我們推測EB病毒溶裂期蛋白質Zta所誘發的介白質13可以幫助B細胞的增生，進而促進了何杰金氏淋巴癌的生長以及一些EB病毒相關的淋巴增生疾病的產生。

Epstein-Barr virus (EBV) infection can alter the cytokine expression profiles of host cells and determine the fate of those cells. Of note, interleukin-13 (IL-13) was detected in EBV-associated Hodgkin’s lymphoma biopsies. The amounts of IL-13 in the plasma of NK cell type chronic active EBV-infection patients are also elevated, but its biological role and regulatory mechanism are not understood. Using cytokine antibody arrays, we found that IL-13 production is induced in B cells after EBV infection. Further investigation indicates that EBV lytic protein, Zta, which is a transactivator, directly activates IL-13 expression following transfection. The mechanism underlying Zta-mediated induction of IL-13 is through direct binding of Zta to the IL-13 promoter, via a consensus AP-1 binding site to transactivate IL-13 expression. Blockade of IL-13 by its neutralization antibody shows an inhibition of cell proliferation in EBV-infected primary B cells and EBV-immortalized lymphoblastoid cell lines (LCLs), indicating the importance of IL-13 in the early stage of EBV-induced cell proliferation and in long-term maintenance of cell growth. Our data suggest Zta-induced IL-13 production facilitates B-cell proliferation and may contribute to the pathogenesis of Hodgkin’s lymphoma and EBV-associated lymphoproliferative diseases (LPD).