Lyons Caitriona, Fernandes Philana, Fanning Liam J, Houston Aileen, Brint Elizabeth
Department of Pathology, University College Cork, Cork, Ireland.
Department of Medicine, University College Cork, Cork, Ireland.
PLoS One. 2015 Apr 7;10(4):e0123635. doi: 10.1371/journal.pone.0123635. eCollection 2015.
Viral double-stranded RNA (dsRNA) is recognised by pathogen recognition receptors such as Toll-Like Receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I), and results in cytokine and interferon production. Fas, a well characterised death receptor, has recently been shown to play a role in the inflammatory response. In this study we investigated the role of Fas in the anti-viral immune response. Stimulation of Fas on macrophages did not induce significant cytokine production. However, activation of Fas modified the response of macrophages to the viral dsRNA analogue poly I:C. In particular, poly I:C-induced IP-10 production was significantly enhanced. A similar augmentation of IP-10 by Fas was observed following stimulation with both poly A:U and Sendai virus. Fas activation suppressed poly I:C-induced phosphorylation of the MAP kinases p38 and JNK, while overexpression of the Fas adaptor protein, Fas-associated protein with death domain (FADD), activated AP-1 and inhibited poly I:C-induced IP-10 production. Consistent with an inhibitory role for AP-1 in IP-10 production, mutation of the AP-1 binding site on the IP-10 promoter resulted in augmented poly I:C-induced IP-10. These results demonstrate that engagement of the Fas receptor plays a role in modifying the innate immune response to viral RNA.
病毒双链RNA（dsRNA）可被病原体识别受体如Toll样受体3（TLR3）和视黄酸诱导基因I（RIG-I）识别，并导致细胞因子和干扰素的产生。Fas是一种特征明确的死亡受体，最近已被证明在炎症反应中起作用。在本研究中，我们调查了Fas在抗病毒免疫反应中的作用。刺激巨噬细胞上的Fas并未诱导显著的细胞因子产生。然而，Fas的激活改变了巨噬细胞对病毒dsRNA类似物聚肌胞苷酸（poly I:C）的反应。特别是，poly I:C诱导的IP-10产生显著增强。在用聚腺苷酸:尿苷酸（poly A:U）和仙台病毒刺激后，观察到Fas对IP-10有类似的增强作用。Fas激活抑制了poly I:C诱导的丝裂原活化蛋白激酶p38和JNK的磷酸化，而Fas衔接蛋白、死亡结构域相关蛋白（FADD）的过表达激活了AP-1并抑制了poly I:C诱导的IP-10产生。与AP-1在IP-10产生中的抑制作用一致，IP-10启动子上AP-1结合位点的突变导致poly I:C诱导的IP-10增加。这些结果表明，Fas受体的激活在改变对病毒RNA的固有免疫反应中起作用。
