TY - JOUR
T1 - Double-stranded RNA-induced interferon-beta and inflammatory cytokine production modulated by hepatitis C virus serine proteases derived from patients with hepatic diseases
AU - Dansako, Hiromichi
AU - Ikeda, Masanori
AU - Ariumi, Yasuo
AU - Wakita, Takaji
AU - Kato, Nobuyuki
N1 - Funding Information:
We would like to thank T. Maeta, K. Takemoto, and T. Nakamura for their technical assistance. K. Naka and S. Ohkoshi are also thanked for their valuable input in this study. This work was supported by Grants-in-Aid for the Third-Term Comprehensive Ten-Year Strategy for Cancer Control, and by a Grant-in-Aid for Research on Hepatitis, both from the Ministry of Health, Labor, and Welfare of Japan.
PY - 2009/5
Y1 - 2009/5
N2 - We previously demonstrated that hepatitis C virus (HCV) serine protease NS3-4A was unable to cleave TRIF (adaptor protein of Toll-like receptor 3), resulting in a lack of suppression of the TRIF-mediated pathway, whereas NS3-4A cleaved Cardif (adaptor protein of retinoic acid-inducible gene I or melanoma differentiation-associated gene-5), resulting in an interruption of the Cardif-mediated pathway in non-neoplastic human hepatocyte PH5CH8 cells. To elucidate these observations, we examined the cleavage potential of NS3-4A for TRIF in PH5CH8 cells, genome-length HCV RNA-replicating O cells, and HCV-infected cells, and we demonstrated that NS3-4A lacked the ability to cleave endogenous TRIF, regardless of HCV strains derived from patients with different stages of hepatic disease. Furthermore, we demonstrated that inflammatory cytokine production by NF-κB activation via the TRIF-mediated pathway also remained unsuppressed by NS3-4A. These results suggest that the inhibitory effects of NS3-4A on antiviral signaling pathways are limited to the Cardif-mediated pathway in human hepatocytes.
AB - We previously demonstrated that hepatitis C virus (HCV) serine protease NS3-4A was unable to cleave TRIF (adaptor protein of Toll-like receptor 3), resulting in a lack of suppression of the TRIF-mediated pathway, whereas NS3-4A cleaved Cardif (adaptor protein of retinoic acid-inducible gene I or melanoma differentiation-associated gene-5), resulting in an interruption of the Cardif-mediated pathway in non-neoplastic human hepatocyte PH5CH8 cells. To elucidate these observations, we examined the cleavage potential of NS3-4A for TRIF in PH5CH8 cells, genome-length HCV RNA-replicating O cells, and HCV-infected cells, and we demonstrated that NS3-4A lacked the ability to cleave endogenous TRIF, regardless of HCV strains derived from patients with different stages of hepatic disease. Furthermore, we demonstrated that inflammatory cytokine production by NF-κB activation via the TRIF-mediated pathway also remained unsuppressed by NS3-4A. These results suggest that the inhibitory effects of NS3-4A on antiviral signaling pathways are limited to the Cardif-mediated pathway in human hepatocytes.
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U2 - 10.1007/s00705-009-0375-z
DO - 10.1007/s00705-009-0375-z
M3 - Article
C2 - 19353241
AN - SCOPUS:65549143094
VL - 154
SP - 801
EP - 810
JO - Archives of Virology
JF - Archives of Virology
SN - 0304-8608
IS - 5
ER -