Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 294, Issue 2, Pages 414-422Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/S0006-291X(02)00502-8
Keywords
hepatitis C; hepatitis B; IFN, IL-1 beta; IL-10; cytokines; crosstalk; STAT
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Crosstalk between interferons (IFNs) and several cytokines is likely to play an important role in viral clearance in chronic hepatitides B and C. We investigated the influence of this phenomenon on IFN-inducible antiviral gene expression in HuH-7 human hepatoma cells. HuH-7 cells were treated with IFN-alpha in the absence or presence of interleukin-1beta (IL-1beta) or IL-10 and the expression of antiviral genes such as 2'5'-oligoadenylate synthetase (2'5'-OAS) and double-stranded RNA-dependent protein kinase (PKR), as well as activation of signal transducer and activator of transcription I (STAT1), a key step for relaying the IFN-alpha signals, was analyzed by Northern blotting, Western blotting, and the reporter gene transfection assay. IL-1beta potentiated IFN-alpha-induced 2'5'-OAS and PKR gene expression, similar to expression of the transfected reporter genes containing the IFN-stimulated regulatory elements, while IL-10 suppressed IFN-alpha-stimulated gene expression. With regard to IFN-alpha signaling, IL-1beta enhanced both tyrosine and serine phosphorylation of STAT1 through p38 mitogen-activated protein kinase activation. In contrast, IL-10 inhibited IFN-alpha-mediated tyrosine phosphorylation of STAT1 by induction of a Janus kinase inhibitor, JAB. IL-1beta and IL-10 interact with IFN-alpha to up- and down-regulate antiviral gene expression, respectively, by modulating STAT1 activation induced by IFN-alpha. (C) 2002 Elsevier Science (USA). All rights reserved.
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