Guarding the frontiers: the biology of type III interferons

Abstract

Type III interferons (IFNs) or IFN-λs regulate a similar set of genes as type I IFNs, but whereas type I IFNs act globally, IFN-λs primarily target mucosal epithelial cells and protect them against the frequent viral attacks that are typical for barrier tissues. IFN-λs thereby help to maintain healthy mucosal surfaces through immune protection, without the significant immune-related pathogenic risk associated with type I IFN responses. Type III IFNs also target the human liver, with dual effects: they induce an antiviral state in hepatocytes, but specific IFN-λ4 action impairs the clearance of hepatitis C virus and could influence inflammatory responses. This constitutes a paradox that has yet to be resolved.

Innate Antiviral Defenses Independent of Inducible IFNα/β Production

“…Interestingly, type III IFNs (IFNl), which are induced through the same pathways as type I IFNs and induce largely the same set of genes [33], act preferentially on epithelial surfaces, due to the restricted expression of the IFNl receptor chain IL28RA by epithelial cells [56,57]. Mice infected in the airways with influenza A virus or in the gastrointestinal tract with reovirus or rotavirus rely on IFNl to fully control the infection [58][59][60][61].…”

Host – hepatitis C viral interactions: The role of genetics

“…Genome wide association studies (GWAS) revealed a strong association of genetic variants near the interleukin 28B (IL28B) gene with spontaneous and pegylated interferon alpha (PegIFNa) treatment-induced clearance of HCV [7][8][9][10][11][12]. IL28B corresponds to interferon (IFN)k3, and more recently it has become clear that the functional single nucleotide polymorphisms (SNPs) are in the newly discovered INFk4 gene that is located next to IFNk3 (IL28B) on human chromosome 19q13 [13]. In 2016, with the increasing availability of, and access to highly effective antiviral regimens for the treatment of CHC, the relevance of host genetic variation to the outcome of treatment is diminishing.…”

Cellular and molecular regulation of innate inflammatory responses

“…1,2 This recognition triggers a series of signaling cascades that culminate in activation of transcriptional factors nuclear factor-κB (NF-κB), interferon regulatory factor (IRF) and activator protein-1 (AP-1), which induce numerous downstream genes encoding a broad range of inflammatory cytokines, chemokines, antimicrobial peptides, complement factors and interferons. 3,4 TLRs are type I transmembrane molecules which transduce their downstream signaling through the MyD88-dependent pathway or the MyD88-independent but TRIF-dependent pathway, subsequently leading to activation of mitogenactivated protein kinase (MAPK), NF-κB and IRF pathway, inducing the production of proinflammatory cytokines and IFNs (Figure 1). [5][6][7][8] Innate immune activation of phagocytes through TLRs also induces an Mst1-Mst2-Rac signaling axis to activate intracellular microbicidal killing.…”