Imiquimod suppresses propagation of herpes simplex virus 1 by upregulation of cystatin A via the adenosine receptor A1 pathway.
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.
Department of Dermatology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Yuji
Y
Kan
Tamaki
T
Okabayashi
Shin-ichi
S
Yokota
Soh
S
Yamamoto
Nobuhiro
N
Fujii
Toshiharu
T
Yamashita
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D055312:Cystatin A / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000378:metabolism*; D006801:Humans; D000077271:Imiquimod; D007372:Interferons / Q000378:metabolism; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000096:biosynthesis; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D055312:Cystatin A; D034741:RNA, Small Interfering; D043682:Receptor, Adenosine A1; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D007372:Interferons; D000077271:Imiquimod