Imiquimod Suppresses Propagation of Herpes Simplex Virus 1 by Upregulation of Cystatin A via the Adenosine Receptor A1 Pathway
Imiquimod Suppresses Propagation of Herpes Simplex Virus 1 by Upregulation of Cystatin A via the Adenosine Receptor A1 Pathway
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DOI：
10.1128/jvi.01196-12
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发表时间：
2012-10-01
影响因子：
5.4
通讯作者：
Yamashita, Toshiharu
中科院分区：
文献类型：
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作者：
Kan, Yuji;Okabayashi, Tamaki;Yamashita, Toshiharu
咪喹莫特被认为是免疫活性细胞中 Toll 样受体 7 (TLR7) 的激动剂。 TLR7 以及 TLR3 和 TLR8 可触发免疫反应，例如通过识别受感染细胞中的病毒核酸来产生 I 型干扰素 (IFN) 和促炎细胞因子。在这项研究中，我们提出咪喹莫特在非免疫细胞中具有不依赖于干扰素的抗病毒作用。咪喹莫特（而非瑞喹莫特）抑制 FL 细胞中人类单纯疱疹病毒 1 (HSV-1) 的复制。我们使用微阵列分析分析了咪喹莫特治疗后基因表达的改变。在咪喹莫特处理的 FL 细胞中，I 型 IFN、TLR 和 IFN 诱导的抗病毒基因都没有被诱导。半胱氨酸蛋白酶抑制剂 A 是一种宿主半胱氨酸蛋白酶抑制剂，可被咪喹莫特强烈上调，并在使用其小干扰 RNA 的抑制实验推断出的抗 HSV-1 活性中起主要作用。半胱氨酸蛋白酶抑制剂 A 的上调被认为是通过拮抗腺苷受体 A(1) 和激活蛋白激酶 A 途径介导的。咪喹莫特（而非雷西莫特）显示与腺苷受体 A(1) 相互作用。在其他细胞（如 HeLa、SiHa 和 CaSki 细胞）中观察到咪喹莫特诱导的抗 HSV-1 活性，其方式与咪喹莫特诱导胱抑素 A 一致。这些结果表明咪喹莫特作为腺苷受体 A(1) 的拮抗剂并诱导宿主抗病毒蛋白胱抑素 A。该过程独立于 TLR7 和 I 型 IFN 发生。
Imiquimod is recognized as an agonist for Toll-like receptor 7 (TLR7) in immunocompetent cells. TLR7, as well as TLR3 and TLR8, triggers the immune responses, such as the production of type I interferons (IFNs) and proinflammatory cytokines via recognition of viral nucleic acids in the infected cells. In this study, we proposed that imiquimod has an IFN-independent antiviral effect in nonimmune cells. Imiquimod, but not resiquimod, suppressed replication of human herpes simplex virus 1 (HSV-1) in FL cells. We analyzed alternation of gene expression by treatment with imiquimod using microarray analysis. Neither type I IFNs, nor TLRs, nor IFN-inducible antiviral genes were induced in imiquimod-treated FL cells. Cystatin A, a host cysteine protease inhibitor, was strongly upregulated by imiquimod and took a major part in the anti-HSV-1 activity deduced by the suppression experiment using its small interfering RNA. Upregulation of cystatin A was suggested to be mediated by antagonizing adenosine receptor A(1) and activating the protein kinase A pathway. Imiquimod, but not resiquimod, was shown to interact with adenosine receptor A(1). Imiquimod-induced anti-HSV-1 activity was observed in other cells, such as HeLa, SiHa, and CaSki cells, in a manner consistent with the cystatin A induction by imiquimod. These results indicated that imiquimod acted as an antagonist for adenosine receptor A(1) and induced a host antiviral protein, cystatin A. The process occurred independently of TLR7 and type I IFNs.