Ethanol Inhibition: The Humoral and Cellular Immune Response to Hepatitis C Virus NS5 Protein After Genetic Immunization

Encke, Jens; Wands, J

doi:10.1097/00000374-200007000-00018

Cited by 20 publications

(26 citation statements)

References 43 publications

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“…The immunosuppressive effects of ethanol have been extensively studied, and it has been shown that chronic ethanol consumption causes broad immunosuppression, such as reduction of the viral-specific-induced cytotoxic T-lymphocyte and naturalkiller activity. 25,26 Second, ethanol directly inhibits the IFN-␣-activated signals by p42/44MAP kinase and PKC-dependent mechanisms. 27 Third, chronic ethanol consumption inhibits IFN therapy by induction of a wide variety of cytokines, including tumor necrosis factor ␣ (TNF-␣), interleukin (IL)-1, IL-8, and IL-10.…”

Section: Discussionmentioning

confidence: 99%

Expression of interferon alfa signaling components in human alcoholic liver disease

Nguyễn

Gao

2002

Hepatology

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Interferon alfa (IFN-␣) is currently the only well-established therapy for viral hepatitis. However, its effectiveness is much reduced (<10%) in alcoholic patients. The mechanism underlying this resistance is not fully understood. In this study, we examined the expression of IFN-␣ signaling components and its inhibitory factors in 9 alcoholic liver disease (ALD) and 8 healthy control liver tissues. In comparison with normal control livers, expression of IFN-␤, IFN-␣ receptor 1/2, Jak1, and Tyk2 remained unchanged in ALD livers, whereas expression of IFN-␣, signal transducer and activator of transcription factor 1 (STAT1), and p48 were up-regulated and expression of STAT2 was down-regulated. I nterferon alfa (IFN-␣) therapy is the primary choice of treatment for viral hepatitis, a disease that affects millions of people worldwide. 1,2 IFN-␣ exerts an antiviral effect by modulating the immune system, including regulating antigen processing and presentation, and stimulating the development of specific T-helper-cell subsets. 3,4 In addition to modulation of the immune system, IFN directly eradicates the virus by stimulating production of endogenous antiviral proteins such as double-stranded RNA-activated protein kinase R (PKR), 2Ј-5Ј oligoadenylate synthetase (OAS), and MxA, a karyophilic 75 kd protein induced by IFN in mouse cells carrying the influenza virus resistance allele Mx ϩ through the Janus kinase (Jak)-signal transducer and activator of transcription factor (STAT) signaling cascade. 3,4 IFN-␣/␤ signaling begins with ligation and dimerization of the corresponding IFN-␣/␤ receptors (IFN␣R1 and IFN␣R2). Receptor dimerization induces autophosphorylation of the receptor-associated JAKs, Jak1 and Tyk2. These activated kinases also phosphorylate the receptor to recruit SH2 domain-containing STATs (STAT1 and STAT2) from the cytosol to the membrane to be phosphorylated. Once activated, STATs are released back into the cytosol for dimerization. Stat1:Stat2 heterodimers translocate into the nucleus, where they bind a third component, p48, forming the ISGF3 transcription factor complex that binds the interferonstimulated response element to initiate transcription of IFN-␣/␤-specific genes. 3,4 Several mechanisms have been implicated in down-regulation of IFN-␣/␤ signaling. Protein tyrosine phosphatases (PTPs) such as Shp-1, Shp-2, and CD45 phosphatase have been shown to dephosphorylate IFN␣R and JAKs, respectively. 5-8 A family of suppressors of cytokine signaling (SOCS) inhibitory proteins has been recently identified and shown to inhibit IFN signaling by targeting JAKs. 9 The JAK-STAT signaling pathway is also inhibited by activation of several kinases, including p42/44 MAP kinase, protein kinase C (PKC) and protein kinase A. [10][11][12][13] Although IFN-␣ has been used for the treatment of viral hepatitis for more than a decade, unfortunately, more than 60% to 70% of patients respond poorly. 14-16 Most patients experience

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Section: Discussionmentioning

confidence: 99%

Expression of interferon alfa signaling components in human alcoholic liver disease

Nguyễn

Gao

2002

Hepatology

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“…These observations were recapitulated in several animal studies. For instance, mice chronically exposed to ethanol generate reduced CD4 and CD8 T cell responses, with diminished proliferation, cytotoxicity and T-helper 1 (Th1) cytokine production following immunization with HCV antigen [3,4]. Similarly, chronic ethanol exposure also results in ablated CD8 T cell responses and a shift to Th2 responses in mice following infection with Listeria monocytogenes [5,6].…”

Section: Introductionmentioning

confidence: 99%

Moderate alcohol consumption enhances vaccine-induced responses in rhesus macaques

Messaoudi

Asquith

Engelmann

et al. 2013

Vaccine

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We have recently shown that chronic alcohol consumption in a rhesus macaque model of ethanol self-administration significantly modulates the serum cytokine profile. In this study, we extended these observations by investigating the impact of chronic ethanol exposure on the immune response to Modified Vaccinia Ankara (MVA). All animals were vaccinated with MVA before ethanol exposure to ethanol and then again after 7 months of 22 h/day of “open-access” drinking of 4% (w/v) ethanol. Our results indicate that animals whose blood ethanol concentration (BEC) chronically exceeded 80 mg/dl had lower CD4 and CD8 T cell proliferation as well as IgG responses following MVA booster than control animals. In contrast, relatively moderate drinkers whose BEC remained below 80 mg/ml exhibited more robust MVA-specific IgG and CD8 T cell responses than controls. To begin to uncover mechanisms underlying the differences in MVA-specific responses between the three groups, we analyzed plasma cytokine levels and microRNA expression in peripheral blood mononuclear cells following MVA booster. Our findings suggest that moderate ethanol consumption results in higher levels of antiviral cytokines and an expression profile of microRNAs linked to CD8 T cell differentiation. In summary, moderate alcohol consumption enhances recall vaccine responses, whereas chronic alcohol intoxication suppresses this response.

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“…Longterm ethanol ingestion may broadly influence immunity (5,6). Previous experimental studies suggest that CD4 1 T cell proliferation and cytotoxic T-lymphocyte (CTL) activity responses to NS5 or hepatitis C virus (HCV) core proteins were suppressed by chronic ethanol consump-tion (3,7,8). Further investigations reveal that viral antigen specific impairment of CD4 1 T cell proliferation and CTL activity may be restored by interleukin (IL)-2 and granulocyte-macrophage colony-stimulating factor additions (7,8).…”

Section: Introductionmentioning

confidence: 99%

Chronic alcohol-induced liver disease inhibits dendritic cell function

Feng

Eken

Ortiz

et al. 2011

Liver International

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Background/Aims We have compared dendritic cell (DC) function derived from the alcoholic liver disease (ALD) sensitive Long–Evans (LE) and resistant Fischer rat strains to determine if the influence of ethanol on DCs was dependent on ALD. Methods The LE and Fischer rats were fed an ethanol-containing or isocaloric control liquid diet for 8 weeks and comparisons were made to LE rats injected with thioacetamide as a liver disease control. DCs were isolated from the spleen after expansion with human Fms-like tyrosine kinase receptor 3 ligand plasmid. Maturation markers CD86, CD80, CD40 and MHC-II were analysed by flow cytometry with or without lipopolysaccharide and poly I:C stimulation. Production of tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-12p40 and IL-10 cytokines and the antigen presentation ability of DCs was determined. Results Only LE rats developed ALD characterized by liver injury, elevated alanine aminotransferase levels and steatosis; CD86 and CD40 expression was decreased in LE but not Fischer rats. Reduced TNF-α, IFN-γ, IL-12, proinflammatory and enhanced IL-10 cytokine production was found in DCs isolated from ethanol-fed LE but not Fischer rats. Allostimulatory activity was reduced in LE compared with the Fischer strain. In contrast, DCs isolated from thioacetamide-induced liver damage displayed a reduction only in IL-12p40; TNF-α, IL-10 and IFN-α production as well as antigen presenting ability remained intact compared with controls. Conclusions ALD sensitive LE rats exhibited characteristics of a suppressed DC phenotype that was not observed following thioacetamide-induced liver disease, which suggests an important role for ALD in altering the host cellular and humoral immune responses.

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Ethanol Inhibition: The Humoral and Cellular Immune Response to Hepatitis C Virus NS5 Protein After Genetic Immunization

Abstract: These results suggest that the high rate of chronic HCV infection in alcoholics may be due to ethanol's effects on antiviral immune responses.

Cited by 20 publications

References 43 publications

Expression of interferon alfa signaling components in human alcoholic liver disease

Expression of interferon alfa signaling components in human alcoholic liver disease

Moderate alcohol consumption enhances vaccine-induced responses in rhesus macaques

Chronic alcohol-induced liver disease inhibits dendritic cell function

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