Differential gene induction by type I and type II interferons and their combination

Type I and type II interferons (IFNs) bind to different cell surface receptors but activate overlapping signal transduction pathways. We examined the effects of a type I IFN (IFN-αcon1) and a type II IFN (IFN-γ1b) on gene expression in A549 cells and demonstrate that there is a common set of genes modulated by both IFNs as well as a set of genes specifically regulated by each, reflecting the activation of different signaling pathways. In particular, IFN-γ induced many more genes of the signaling pathways, apoptosis, and cytokine interactions than did IFN-α. Even with genes induced by both IFNs there were distinctive quantitative differences in expression. IFN-γ1b plays a major role in the induction and regulation of the complement pathway. Previous work has shown a synergistic antiviral and antiproliferative effect of type I and type II IFNs in cell culture and in the treatment of tumors in mice. We demonstrate that a majority of genes showed an additive effect of IFN-αcon1 and IFN-γ1b, but a subset of genes is synergistically induced; these include ISG20, MX2, OAS2, and other genes known to be involved in the antiviral response, TRAIL (TNFSF10) and caspases involved in apoptosis and chemokine genes RANTES, CXCL10, and CXCL11. Greater than additive transcription of some of these genes in the presence of both IFNs was confirmed by real-time kinetic RT-PCR. Elevated induction of many of these genes may be sufficient to explain the synergistic antiviral and antitumor effects of this combination of IFNs in vivo.