Interferons (IFNs) have been used in the treatment of viral hepatitis. However, their effectiveness is much reduced (< 10%) in alcoholics. The mechanism underlying this resistance remains unknown. Here, we report that IFN-α/β and IFN-γ rapidly activate the JAK-STAT1 (Janus kinase-signal transducer and activator transcription factor 1) and p42/44 mitogen-activatedprotein kinase (p42/44 MAPK) in freshly isolated rat hepatocytes. Treatment of hepatocytes with 25-100 mM ethanol for 30 min inhibited IFN-β- or IFN-γ-induced STAT1 activation and tyrosine phosphorylation. The inhibitory effect of ethanol was not reversed by pretreatment with either sodium vanadate, a non-selective tyrosine phosphatase inhibitor, or with MG132, a specific proteasome inhibitor. This suggests that protein tyrosine phosphatases or the ubiquitin-proteasome pathway are not involved in the inhibitory action of ethanol. In contrast with the JAK-STAT signalling pathway, acute ethanol exposure significantly potentiated IFN-β or IFN-γ-induced activation of p42/44 MAPK, and caused marked activation of protein kinase C (PKC). Inhibition of PKC partially antagonized ethanol attenuation of IFN-induced STAT1 activation, suggesting that PKC may be involved. Taken together, these findings suggest that the ability of biologically relevant concentrations of ethanol (less than 100 mM) to markedly inhibit IFN-activated STAT1 is one of the cellular mechanisms responsible for the observed resistance of IFN therapy in alcoholics.
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Research Article|
July 10 2000
Interferons activate the p42/44 mitogen-activated protein kinase and JAK-STAT (Janus kinase-signal transducer and activator transcription factor) signalling pathways in hepatocytes: differential regulation by acute ethanol via a protein kinase C-dependent mechanism
Van-Anh T. NGUYEN;
Van-Anh T. NGUYEN
1Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, U.S.A.
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Jianping CHEN;
Jianping CHEN
1Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, U.S.A.
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Feng HONG;
Feng HONG
1Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, U.S.A.
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Edward J. N. ISHAC;
Edward J. N. ISHAC
1Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, U.S.A.
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Publisher: Portland Press Ltd
Received:
January 10 2000
Revision Received:
April 28 2000
Accepted:
May 10 2000
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 2000
2000
Biochem J (2000) 349 (2): 427–434.
Article history
Received:
January 10 2000
Revision Received:
April 28 2000
Accepted:
May 10 2000
Citation
Van-Anh T. NGUYEN, Jianping CHEN, Feng HONG, Edward J. N. ISHAC, Bin GAO; Interferons activate the p42/44 mitogen-activated protein kinase and JAK-STAT (Janus kinase-signal transducer and activator transcription factor) signalling pathways in hepatocytes: differential regulation by acute ethanol via a protein kinase C-dependent mechanism. Biochem J 15 July 2000; 349 (2): 427–434. doi: https://doi.org/10.1042/bj3490427
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