Expression of interferon alfa signaling components in human alcoholic liver disease.
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.
Nguyen
Van-Anh
VA
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Gao
Bin
B
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000502:physiology*; D016899:Interferon-beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D008099:Liver / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000503:physiopathology*; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D064547:Myxovirus Resistance Proteins; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000378:metabolism; D012016:Reference Values; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D019892:eIF-2 Kinase / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; C579071:MX1 protein, human; D008565:Membrane Proteins; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D011506:Proteins; D017471:Receptors, Interferon; D012097:Repressor Proteins; C108944:SOCS1 protein, human; C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C491590:Socs1 protein, mouse; C491409:Socs2 protein, mouse; C491411:Socs3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D019892:eIF-2 Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015088:2',5'-Oligoadenylate Synthetase; D017027:Protein Tyrosine Phosphatases; D019204:GTP-Binding Proteins