Effects of inhibitors of Toll-like receptors, protease-activated receptor-2 signalings and trypsin on influenza A virus replication and upregulation of cellular factors in cardiomyocytes
Effects of inhibitors of Toll-like receptors, protease-activated receptor-2 signalings and trypsin on influenza A virus replication and upregulation of cellular factors in cardiomyocytes
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DOI：
10.2152/jmi.58.19
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发表时间：
2011-02-01
影响因子：
0.7
通讯作者：
Kido, Hiroshi
中科院分区：
文献类型：
--
作者：
Pan, Hai-Yan;Yano, Mihiro;Kido, Hiroshi
严重的流行性感冒有时会引起心肌炎。我们最近发现甲型流感病毒（IAV）感染诱导多种细胞因子，如促炎细胞因子IL-6、IL-1 β和TNF-α、基质金属蛋白酶（MMPs）和小鼠心脏和H9 c2心肌细胞中的异位胰蛋白酶。这些细胞因子的诱导反过来促进病毒复制，心肌炎症和细胞损伤，通过其细胞内信号转导与IAV诱导的Toll样受体（TLR）和蛋白酶激活受体-2（PAR-2）信号转导合作，尽管这些相互作用的确切性质仍然不清楚。本研究采用TLR和PAR-2信号通路特异性抑制剂及胰蛋白酶抑制剂抑肽酶，分析TLR和PAR-2信号通路在IAV诱导心肌细胞病变中的作用。TLR 7/8-髓样分化因子88-核因子-chi B信号传导和抑肽酶的抑制剂有效地抑制了IAV诱导的促炎细胞因子、MMPs、胰蛋白酶原和病毒复制的上调。诱导干扰素依赖性信号传导的含有TLR 3-Toll/白细胞介素-1受体结构域的衔接子的抑制剂主要抑制干扰素-β（一种关键的细胞内宿主免疫应答因子）的上调。与胰蛋白酶抑制剂抑肽酶对IAV复制的抑制作用相反，PAR-2抑制剂FSY-NH 2诱导胰蛋白酶原的边缘上调和随后的IAV复制刺激。
Severe influenza sometimes causes myocarditis. We recently found that influenza A virus (IAV) infection induces various cellular factors, such as proinflammatory cytokines IL-6, IL-1 beta and TNF-alpha, matrix metalloproteinases (MMPs) and ectopic trypsin in mice hearts and in H9c2 cardiomyocytes. The induction of these cellular factors in turn promotes viral replication, myocardial inflammation and cellular damage through their intracellular signal transductions in cooperation with the IAV-induced Toll-like receptors (TLRs) and proteinase-activated receptor-2 (PAR-2) signallings, although the precise nature of these interactions remain obscure. By using specific inhibitors of TLRs and PAR-2 signalings and trypsin inhibitor aprotinin, we analyzed the role of TLR signaling and PAR-2 signaling in the IAV-induced pathological changes in cardiomyocytes. Inhibitors of TLR7/8-Myeloid Differentiation factor 88-nuclear factor-chi B signaling and aprotinin effectively suppressed IAV-induced upregulation of proinflammatory cytokines, MMPs, trypsinogen and viral replication. Inhibitor of TLR3-Toll/interleukin-1 receptor domain-containing adaptor inducing interferons-dependent signaling predominantly suppressed the upregulation of interferon-beta, a key intracellular host immune response factor. In contrast to the suppressive effect of trypsin inhibitor aprotinin on IAV replication, PAR-2 inhibitor FSY-NH2, induced marginal upregulation of trypsinogen and subsequent stimulation of IAV replication.