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

Abstract

See Articles on Pages 1250 and 1262 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.1 IFN cytokines are commonly classified into distinct families, based on their structural properties and on the receptor complex through which they signal.1 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.2-4 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 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. 6 Despite what appear to be common signaling cascades, type I and III IFNs have begun to reveal divergent biological activities.7-10 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. 11,12These 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. 8,13,14 In the current experiments, transcriptome analysis from human hepatoma Huh7 cells or pri...

IFN‐λ‐mediated IL‐12 production in macrophages induces IFN‐γ production in human NK cells

“…In contrast, the restricted expression of IFN-λR1 prevented a direct action of IFN-λ on both NK cells and monocytes, with only responses observed on differentiated macrophages. This suggests that IFN-λ might play a more prominent role in tissue-specific responses as compared to the periphery, in line with other studies describing that IFN-λ1 has a more delayed and prolonged effect through activation of specific tissue-resident cells, specifically epithelial cells and hepatocytes [25,26]. TLR-dependent crosstalk between NK cells and macrophages has already been described in tissue-specific interactions in the liver.…”

“…The delayed activation of NK cells by IFN-λ, mediated through macrophage IL-12 production, could explain the observed differences in biological functions between the type I and type III IFNs in inflammatory responses, but also by differences in kinetics or sustainability of the response. It should be noted that a similar kinetic on innate immune response activation by type III IFNs has been previously described for DCs and hepatocytes [26,30,38].…”

“…The delayed activation of NK cells by IFN-λ, mediated through macrophage IL-12 production, could explain the observed differences in biological functions between the type I and type III IFNs in inflammatory responses, but also by differences in kinetics or sustainability of the response. It should be noted that a similar kinetic on innate immune response activation by type III IFNs has been previously described for DCs and hepatocytes [26,30,38].Collectively, this study provides the first example of an indirect regulatory effect unique to IFN-λ1, mediated through macrophage cytokine production and independent of cell-to-cell contact. This is distinct from IFN-α, which directly activates NK cells, and can inhibit macrophage IL-12 production.…”

“…At present, it is unclear how triggering of similar signaling pathways by IFN-α and IFN-λ results in divergent biological activities. Besides macrophages, further functional differences have been described between IFN-α and IFN-λ in their modulation of hepatocytes, where IFN-λ has been shown to activate a more restricted subset of cells as well as induce sustained interferon-stimulated gene responses [25,26].To further define a role for IFN-λ in antiviral immune responses, the goal of this study was to determine whether IFN-λ could exert any immunomodulatory effects on NK cells, and if so, how that response compared to the action of type I IFNs. A previous study had described IFN-λ as being able to partially inhibit NK-cell-derived IFN-γ production upon IL-12/15 stimulation [27,28], but an effect of IFN-λ on NK cells could not be reproduced in an ensuing response to the original article [29].…”

Treatment of Chronic Hepatitis C with Viral-Suppression linked to Restoration of Innate-Immune Responses with Induction-Therapy with n-IFN-beta followed by Simeprevir

“…Both IFN-beta and IFN-rhamda triggered a sustained ISG response; on the other hand, IFN-alpha produced a kinetic profile of genes that peaked early in the therapy and then rapidly decreased ( Figure 9). No significant difference was observed in STAT1 tyrosine phosphporylation levels between IFN-beta and IFN-alpha, where as serine phosphporylation at position 727 was stimulated more strongly by IFN-beta than by IFN-alpha [29]. The finding that IFN-beta invariably possessed the highest activity among Type I and Type III IFNs suggested that IFN-beta and IFN-rhamda-3 may have superior clinical activity.…”