EB病毒的溶裂期蛋白質在EB病毒相關疾病的發展中扮演某些角色。例如病毒的溶裂期轉活化蛋白質Zta會正向調控發炎相關細胞激素的表現。已知另一個溶裂期轉活化蛋白質Rta可以調控許多病毒溶裂期基因的表現，但它對於宿主細胞基因的調控則較少被探討。特別的是，已有研究指出Rta可以誘發細胞衰老，而細胞衰老通常會伴隨著分泌多種免疫調節性的細胞激素，這種現象稱為衰老相關分泌表型 (SASP)。因此我們想知道Rta是否可以誘發SASP相關細胞激素的表現。在本研究中，我們發現Rta會誘發至少四種SASP相關細胞激素，包括介白素-6 (IL-6)、巨噬細胞集落刺激因子 (GM-CSF)、以及巨噬細胞發炎蛋白質-1α/β (MIP-1α/β)。在沒有EB病毒感染的鼻咽癌上皮細胞中，Rta可以誘發這四種細胞激素RNA及蛋白質的表現，同時也會活化它們基因啟動子的活性。Rta誘發這四種細胞激素的表現都需要Rta的 C端區域，然而Rta可以不需要入核訊號便能誘發IL-6的表現。此外，我們也發現Rta可以活化p38 MAPK並藉此增加甲型雌性激素受體 (ERα) 的表現。抑制劑實驗結果顯示Rta誘發IL-6的表現需要p38 MAPK及ERα。Rta誘發MIP-1α/β的表現需要MAPK、ERα及E2F等多種訊息路徑，但這些路徑卻不參與Rta誘發GM-CSF的表現。總結而論，我們發現Rta可以經由多種機制誘發SASP相關細胞激素的表現，揭露Rta在免疫調控方面的潛在角色。

Epstein-Barr virus (EBV) lytic proteins play certain roles in development of EBV-related diseases. For example, a viral lytic transactivator Zta can upregulate expression of inflammatory cytokines. Rta, another lytic transactivator, is known to regulate many viral lytic genes, but its roles in regulation of cellular genes are less addressed. Notably, Rta has been reported to induce cellular senescence. Considering that cellular senescence is frequently accompanied by secretion of various immunoregulatory cytokines, a state called senescence-associated secretory phenotype (SASP), we wondered if Rta is capable of inducing SASP cytokines. In this study, we found that Rta induced at least four SASP cytokines, including interleukin (IL)-6, granulocyte macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein (MIP)-1α and MIP-1β. In EBV-negative, NPC-derived epithelial cells, Rta increased expression of the four cytokines at both RNA and protein levels, and also activated their gene promoters. The C-terminus of Rta was required for induction of all these cytokines, while the nuclear localization signal of Rta was not essential for IL-6 induction. Furthermore, we found that Rta activated p38 mitogen-activated protein kinase (MAPK) and thus increased expression of estrogen receptor (ER)α. Inhibitor experiments indicated that Rta-triggered IL-6 induction was dependent on both p38 MAPK and ERα. Rta-induced MIP-1α/β expression required MAPK, ERα and E2F signaling pathways, while these pathways were not involved in Rta-induce GM-CSF expression. In conclusion, we demonstrate that Rta can induce SASP cytokines through multiple mechanisms, revealing its potential roles in immune regulation.

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