Type I and type III interferon‐induced immune response: It's a matter of kinetics and magnitude

T he interferon (IFN) family of cytokines, including type I and III IFNs, represent a first line of defense that “interferes” with a vast range of viral infections. IFN cytokines are commonly classified into distinct families, based on their structural properties and on the receptor complex through which they signal. Type I IFNs, including IFN-b and -a, exert their biological activities through a heterodimeric receptor complex known as IFN-a receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. Discovered in 2003, type III IFNs, including interleukin (IL)228A (IFN-k2), IL-28B (IFN-k3), and IL-29 (IFN-k1), are distinct from type I IFNs and act through a different receptor system that is preferentially expressed on the surface of epithelial cells, including hepatocytes. Type III IFNs bind to a heterodimeric receptor consisting of the IL-10 receptor 2 chain and the interferon k receptor 1 (IFNLR1) chain that is structurally different from the IFNAR. Recently, a new coding region upstream of IFNL3 on chromosome 19q13.13, designated as IFNL4, was identified that encodes a new member of the type III IFN family, called IFN-k4. Signaling cascades of both type I and III IFNs converge on the activation of Janus kinase (JAK)1 and tyrosine kinase (TYK)2 kinases, leading to the subsequent phosphorylation and activation of latent signal transducer and activator of transcription (STAT) transcription factors. Phosphorylated STAT1 and STAT2 heterodimerize and interact with IFN regulatory factor 9 (IRF9) to form an IFN-stimulated gene factor 3 (ISGF3) transcription complex that binds to the IFNstimulated response element (ISRE); STAT1 can also homodimerize and bind the gamma-activated sequences (GAS) element. Altogether, binding of these STAT complexes to specific promoter sequences leads to the establishment of an antiviral response through upregulation of hundreds of IFN-stimulated genes (ISGs; Fig. 1), many of which are poorly understood biologically with regard to their antiviral activity. Despite what appear to be common signaling cascades, type I and III IFNs have begun to reveal divergent biological activities. However, it is still unclear whether these related cytokine family members induce common or distinct patterns of ISGs that result in the programming of divergent antiviral and/or immune modulatory states. In this issue of HEPATOLOGY, Bolen et al. and Jilg et al. have approached this question using time-resolved, microarray-based gene expression profiling in human hepatocytes. Both studies reach a similar, but somewhat unpredicted, conclusion that type I and III IFNs stimulate similar sets of ISGs, albeit with very distinct kinetics of response and magnitude of stimulation. These two parallel studies from Bolen et al. and Jilg et al. converge on an answer that contrasts with studies demonstrating that type I and III IFNs induce both overlapping and distinct sets of genes. In the current experiments, transcriptome analysis from human hepatoma Huh7 cells or primary human hepatocytes (PHHs) stimulated with comparable concentrations of IFN-a, -b, -k1, -k2, or -k3 revealed a hierarchy of gene expression, with IFN-b identified as the most biologically active cytokine, followed by IFN-a and IFN-ks (Fig. 1). However, the researchers did not discover any distinct sets of genes modulated by IFN-ks, and all IFN-k-induced genes were also induced by type I IFN, as previously suggested. Although the pattern of gene expression induced by either type I or III IFNs was very similar, the magnitude of the response triggered by IFN-b was more than 10-fold higher than the response promoted by IFN-ks. Bolen et al. also concluded that, among the IFN-k family, IFN-k3 was the most potent ISG inducer and corroborates another study demonstrating that IFN-k3 Abbreviations: GAS, gamma-activated sequences; HCV, hepatitis C virus; IFN, interferon; IFNAR, IFN-a receptor; IFNLR1, interferon k receptor 1; IL, interleukin; IRF9, IFN regulatory factor 9; ISG, IFN-stimulated gene; ISGF3, IFN-stimulated gene factor 3; ISRE, IFN-stimulated response element; JAK, Janus kinase; PHHs, primary human hepatocytes; STAT, signal transducer and activator of transcription; TYK, tyrosine kinase. Address reprint requests to: John Hiscott, Ph.D., Viral Pathogenesis Program, Vaccine and Gene Therapy Institute of Florida, 9801 SW Discovery Way, Port St. Lucie, FL 34987. E-mail: jhiscott@vgtifl.org; fax: 772-345-0625. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26959 Potential conflict of interest: Nothing to report.