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本帖最后由 风雨不动 于 2012-4-14 15:33 编辑
Gastroenterology. 2011 Mar 1. [Epub ahead of print]
Hepatitis B Virus Limits Response of Human Hepatocytes to Interferon-α in
Chimeric Mice. Lütgehetmann M, Bornscheuer T, Volz T, Allweiss L, Bockmann JH,
Pollok JM, Lohse AW, Petersen J, Dandri M. Dept. Internal Medicine, University
Medical Hospital Hamburg-Eppendorf; D-20246 Hamburg, Germany; Department of
Medical Microbiology, Virology and Hygiene, University Medical Hospital
Hamburg-Eppendorf; D-20246 Hamburg, Germany.
Abstract
BACKGROUND & AIMS: Interferon (IFN)-α therapy is not effective for most
patients with chronic hepatitis B virus (HBV) infection, for unclear reasons. We
investigated whether HBV infection reduced IFN-α-mediated induction of
antiviral defence mechanisms in human hepatocytes. METHODS: Human hepatocytes
were injected into severe combined immune deficient mice (SCID/beige) that
expressed transgenic urokinase plasminogen activator under control of the
albumin promoter. Some mice were infected with HBV; infected and uninfected mice
were given injections of human IFN-α. Changes in viral DNA and expression of
human interferon-stimulated genes (ISGs) were measured by real-time PCR, using
human-specific primers, and by immunohistochemistry. RESULTS: Median HBV viremia
(0.8log) and intrahepatic loads of HBV RNA decreased 3-fold by 8 or 12 h after
each injection of IFN-α, but then increased within 24 h. IFN-α activated
expression of human ISGs and nuclear translocation of STAT-1 in human
hepatocytes that repopulated the livers of uninfected mice. Although baseline
levels of human ISGs were slightly increased in HBV-infected mice, compared with
uninfected mice, IFN-α failed to increase expression of the ISGs OAS-1, MxA,
MyD88, and TAP-1 (which regulates antigen presentation) in HBV-infected mice.
Remarkably, IFN-α did not induce nuclear translocation of STAT-1 in
HBV-infected human hepatocytes. Administration of the nucleoside analogue
entecavir (for 20 days) suppressed HBV replication but did not restore
responsiveness to IFN-α. CONCLUSIONS: HBV prevents induction of IFN-α
signaling by inhibiting nuclear translocation of STAT-1; this can interfere with
transcription of ISGs in human hepatocytes. These effects of HBV might
contribute to the limited effectiveness of endogenous and therapeutic IFN-α in
patients and promote viral persistence.Copyright © 2011 AGA Institute.
Published by Elsevier Inc. All rights reserved. PMID: 21376046 [PubMed - as
supplied by publisher]
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发表于 2011-3-15 07:31