Treating chronic hepatitis C virus (HCV) infection using pegylated alpha interferon and ribavirin leads to

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-alphacon1) and a type II IFN (IFN-gamma1b) 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-gamma induced many more genes of the signaling pathways, apoptosis, and cytokine interactions than did IFN-alpha. Even with genes induced by both IFNs there were distinctive quantitative differences in expression. IFN-gamma1b 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-alphacon1 and IFN-gamma1b, 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.

Using oligonucleotide microarrays, we have examined the expression of 22,000 genes in peripheral blood cells treated with pegylated interferon-alpha2b (PEG-IFN-alpha) and ribavirin. Treatment with ribavirin had very little effect on gene expression, whereas treatment with PEG-IFN-alpha had a dramatic effect, modulating the expression of approximately 1000 genes (at p < 0.001). In addition to genes previously reported to be induced by type I or type II IFNs, many novel genes were found to be upregulated, including transcription factors, such as ATF3, ATF4, properdin, a key regulator of the complement pathway, a homeobox gene (HESX1), and an RNA editing enzyme (apobec3). Chemokines CXCL10 and CXCL11 were upregulated, whereas CXCL5 was downregulated. Cytokines interleukin-15 (IL-15) and IL-18 were also significantly induced, whereas IL-1alpha and IL-1beta were downregulated. Most other interleukins were not affected. The results of the microarrays were confirmed by kinetic real-time PCR. These data indicate that IFN treatment causes upregulation of genes associated with the stress response, apoptosis, and signaling, and an equal number of genes are downregulated, including those associated with protein synthesis, specific cytokines and chemokines and other biosynthetic functions.

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