Expression of interferon alfa signaling components in human alcoholic liver disease

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.