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Expression of interferon alfa signaling components in human alcoholic liver disease
1Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Interferon alfa (IFN-alpha) 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-alpha 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-beta, IFN-alpha receptor 1/2, Jak1, and Tyk2 remained unchanged in ALD livers, whereas expression of IFN-alpha, signal transducer and activator of transcription factor 1 (STAT1), and p48 were up-regulated and expression of STAT2 was down-regulated. Expression of antiviral MxA a karyophilic 75 kd protein induced by IFN in mouse cells carrying the influenza virus resistance allele Mx(+) and 2'-5' oligoadenylate synthetase (OAS) proteins was not regulated, whereas expression of double-stranded RNA-activated protein kinase (PKR) was decreased by 55% in ALD livers. Three families of inhibitory factors for the JAK-STAT signaling pathway were examined in ALD livers. Members of the suppressor of cytokine signaling (SOCS) family, including SOCS 1, 2, 3, and CIS, and the protein tyrosine phosphatases, including Shp-1, Shp-2, and CD45, were not up-regulated in ALD livers, whereas the phosphorylation of and protein levels of p42/44 mitogen-activated protein kinase (p42/44MAP kinase) were increased about 3.9- and 3.2-fold in ALD livers in comparison with normal control livers, respectively. In conclusion, these findings suggest that chronic alcohol consumption down-regulates STAT2 and PKR, but up-regulates p42/44 mitogen-activated protein kinase (p42/44MAP kinase), which may cause down-regulation of IFN-alpha signaling in the liver of ALD patients.
Insights
Alcoholic liver disease impairs interferon alfa (IFN-alpha) therapy by altering signaling pathways. Chronic alcohol consumption down-regulates STAT2 and PKR while up-regulating p42/44MAP kinase, hindering IFN-alpha effectiveness.
Area of Science:
- Hepatology
- Immunology
- Molecular Biology
Background:
- Interferon alfa (IFN-alpha) is a primary therapy for viral hepatitis, but its efficacy is significantly reduced in patients with alcoholic liver disease (ALD).
- The molecular mechanisms behind this diminished response to IFN-alpha in ALD remain largely unelucidated.
Purpose of the Study:
- To investigate the expression of key components and inhibitory factors within the IFN-alpha signaling pathway in liver tissues from patients with ALD.
- To identify molecular alterations contributing to IFN-alpha resistance in the context of chronic alcohol consumption.
Main Methods:
- Comparative analysis of gene and protein expression in liver tissues from 9 ALD patients and 8 healthy controls.
- Examination of interferon-stimulated genes (ISGs) like MxA and OAS, and key signaling molecules including STATs, PKR, and MAP kinases.
- Assessment of inhibitory factors such as SOCS and protein tyrosine phosphatases.
Main Results:
- ALD livers showed altered expression of IFN-alpha signaling components: IFN-alpha, STAT1, and p48 were upregulated, while STAT2 was downregulated compared to controls.
- Expression of antiviral proteins MxA and OAS remained unchanged, but double-stranded RNA-activated protein kinase (PKR) expression decreased by 55% in ALD livers.
- Increased phosphorylation and protein levels of p42/44 mitogen-activated protein kinase (p42/44MAP kinase) were observed in ALD livers, alongside unchanged SOCS and phosphatase levels.
Conclusions:
- Chronic alcohol consumption leads to significant alterations in hepatic IFN-alpha signaling pathways.
- Downregulation of STAT2 and PKR, coupled with upregulation of p42/44MAP kinase, likely contributes to the observed resistance to IFN-alpha therapy in ALD patients.
- These findings provide insights into the molecular basis of therapeutic failure and suggest potential targets for improving treatment outcomes in ALD.