Identification of a Predominantly Interferon-λ-Induced Transcriptional Profile in Murine Intestinal Epithelial Cells

Abstract

Type I (α and β) and type III (λ) interferons (IFNs) induce the expression of a large set of antiviral effector molecules via their respective surface membrane receptors. Whereas most cell types respond to type I IFN, type III IFN preferentially acts on epithelial cells and protects mucosal organs such as the lung and gastrointestinal tract. Despite the engagement of different receptor molecules, the type I and type III IFN-induced signaling cascade and upregulated gene profile is thought to be largely identical. Here, we comparatively analyzed the response of gut epithelial cells to IFN-β and IFN-λ2 and identified a set of genes predominantly induced by IFN-λ2. We confirm the influence of epithelial cell polarization for enhanced type III receptor expression and demonstrate the induction of predominantly IFN-λ2-induced genes in the gut epithelium in vivo. Our results suggest that IFN-λ2 targets the epithelium and induces genes to adjust the antiviral host response to the requirements at mucosal body sites.

Comprehensive Proteomics Identification of IFN-λ3-regulated Antiviral Proteins in HBV-transfected Cells

“…those caused over time by differing receptor/ligand affinities and half-lives) versus substantial alterations at the level of pathways and 2) the effects of IFN-3 and IFN-␣2a were indeed substantially similar, especially with regard to canonical IFN effects such as regulation of antiviral proteins, antigen processing/presentation, and the RIG-I signaling pathway. A recent work does make a strong case for a differential 3/␣2a effect on murine intestinal epithelial cells (96), but the effect is pronounced only on polarization of cells, and the underlying microarray data does not correlate with our proteomic data. Thorough studies focused on possible differential effects on PTMs may help resolve these questions; the immediate result of IFN-receptor/ ligand interaction is, after all, a phosphorylation event.…”

Distinct Effects of Type I and III Interferons on Enteric Viruses

“…While there have been a number of successful screens conducted exploring the effects of human ISGs against viruses including West Nile virus and yellow fever virus [ 7 ], these methods have not yet been applied to explore the role of specific ISGs in control of enteric viruses. In addition, the ongoing identification of type III IFN-specific ISGs in responsive cell types has the potential to increase the range of interesting ISGs to test in future assays [ 28 ]. In conclusion, though the past two decades have revealed an enormous amount about the coordinate control of mucosal viruses by different IFNs, there are still many unanswered questions remaining and exciting avenues left to explore.…”

“…Despite use of redundant signaling pathways and similar induction of ISGs between type I and III IFNs [ 25 , 26 , 27 ], recent studies have identified divergent effects of type I and III IFNs. Depending upon the cell type interrogated, type I and III IFNs may mediate differential expression patterns of ISGs, including distinct gene sets induced in intestinal and respiratory epithelial cells [ 28 , 29 ]. Additionally, type I and III IFNs can exhibit differential kinetics of induction, with IFN-α inducing more rapid but transient ISG expression, while the effects of IFN-λ are delayed but longer lasting [ 30 , 31 , 32 ].…”

Lambda interferons come to light: dual function cytokines mediating antiviral immunity and damage control

“…Notably, this pathway is also shared with type I IFNs, highlighting the very similar antiviral activity these two systems exhibit [ 22 , 23 , 24 ]. Thus, it has been difficult to segregate IFNλ from type I IFN functional or transcriptional responses, with IFNλ-induced genes typically representing a subset of all genes elicited by type I IFNs but exhibiting a delayed peak and longer duration [ 23 , 24 , 25 , 26 ].…”