Involvement of IL-1β and IL-10 in IFN-α-mediated antiviral gene induction in human hepatoma cells

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-α in the absence or presence of interleukin-1β (IL-1β) 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 1 (STAT1), a key step for relaying the IFN-α signals, was analyzed by Northern blotting, Western blotting, and the reporter gene transfection assay. IL-1β potentiated IFN-α-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-α-stimulated gene expression. With regard to IFN-α signaling, IL-1β enhanced both tyrosine and serine phosphorylation of STAT1 through p38 mitogen-activated protein kinase activation. In contrast, IL-10 inhibited IFN-α-mediated tyrosine phosphorylation of STAT1 by induction of a Janus kinase inhibitor, JAB. IL-1β and IL-10 interact with IFN-α to up- and down-regulate antiviral gene expression, respectively, by modulating STAT1 activation induced by IFN-α.