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Alcohol attenuates anti-HCV function of IFN-λ1 through up-regulation of PLASy expression in human hepatic cells
- Source :
- Journal of Medical Virology. 90:1112-1120
- Publication Year :
- 2018
- Publisher :
- Wiley, 2018.
-
Abstract
- Alcohol could compromise the anti-hepatitis C virus (HCV) function of interferon-alpha (IFN-α). However, little information is available about the effect of alcohol on interferon-lambda (IFN-λ, type III IFN), a novel candidate for development of therapy for HCV infection. Huh7 cells were infected with HCV JFH-1 virus, then treated with alcohol, and/or IFN-λ1. RT-PCR and Western blot were used to detect the levels of HCV and key cellular factors. Overexpression or silencing expression was performed to verify the role of key factors in alcohol-attenuated anti-HCV function of IFN-λ1. Alcohol treatment compromised anti-HCV effect of IFN-λ1 in HCV JFH-1-infected Huh7 cells, evidenced by the significantly increased levels of HCV RNA, and HCV core protein in alcohol-/IFN-λ1-treated cells compared to cells with IFN-λ1 treatment alone. Investigation of the mechanisms responsible for the alcohol action revealed that alcohol enhanced the expression of protein inhibitor of activated STAT (PIASy). Overexpression of PIASy compromised anti-HCV ability of IFN-λ1, whereas silencing expression of PIASy partly restored the alcohol-attenuated anti-HCV effect of IFN-λ1. More importantly, overexpression of PIASy significantly down-regulated the level of IFN-λ1-indcued phosphorylation of STAT1 (p-STAT1), an important adaptor in IFN-λ pathway, as well as reduced the expression of IFN-λ1-induced IFN-stimulated genes 56 (ISG56), and myxovirus resistance 1 (Mx1), two antiviral effectors in in IFN-λ pathway. These findings indicate that alcohol, through inducing the expression of negative regulator in IFN-λ pathway, inhibits IFN-λ-mediated anti-HCV action in human hepatic cells, which may lead to the poor efficacy of IFN-λ-based therapy against HCV infection.
- Subjects :
- 0301 basic medicine
Hepatitis C virus
Blotting, Western
Hepacivirus
Real-Time Polymerase Chain Reaction
medicine.disease_cause
Virus
Cell Line
03 medical and health sciences
Western blot
Downregulation and upregulation
Virology
medicine
Humans
Gene silencing
Protein inhibitor of activated STAT
STAT1
Poly-ADP-Ribose Binding Proteins
medicine.diagnostic_test
biology
business.industry
Gene Expression Profiling
Interleukins
Viral Core Proteins
Protein Inhibitors of Activated STAT
digestive system diseases
Up-Regulation
030104 developmental biology
Infectious Diseases
Alcohols
Hepatocytes
Cancer research
Hepatic stellate cell
biology.protein
RNA, Viral
Interferons
business
Subjects
Details
- ISSN :
- 01466615
- Volume :
- 90
- Database :
- OpenAIRE
- Journal :
- Journal of Medical Virology
- Accession number :
- edsair.doi.dedup.....b1811a4e84a4903964c7b68077c2fc95