Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Mar 21;20(6):1445.
doi: 10.3390/ijms20061445.

Differential Regulation of Type I and Type III Interferon Signaling

Affiliations
Free PMC article
Review

Differential Regulation of Type I and Type III Interferon Signaling

Megan L Stanifer et al. Int J Mol Sci. .
Free PMC article

Abstract

Interferons (IFNs) are very powerful cytokines, which play a key role in combatting pathogen infections by controlling inflammation and immune response by directly inducing anti-pathogen molecular countermeasures. There are three classes of IFNs: type I, type II and type III. While type II IFN is specific for immune cells, type I and III IFNs are expressed by both immune and tissue specific cells. Unlike type I IFNs, type III IFNs have a unique tropism where their signaling and functions are mostly restricted to epithelial cells. As such, this class of IFN has recently emerged as a key player in mucosal immunity. Since the discovery of type III IFNs, the last 15 years of research in the IFN field has focused on understanding whether the induction, the signaling and the function of these powerful cytokines are regulated differently compared to type I IFN-mediated immune response. This review will cover the current state of the knowledge of the similarities and differences in the signaling pathways emanating from type I and type III IFN stimulation.

Keywords: Interferon; JAK-STAT; interferon signaling; signal transduction; type I IFN; type III IFN.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Type I and III interferon production following pathogen sensing. Schematic representing the canonical pathway of pathogen recognition receptor (PRR) sensing of intracellular pathogens. Pathogen associated molecular patterns (PAMPs) are recognized by PRRs leading to activation and phosphorylation of IRF3/7 which then translocate into the nucleus and drive the expression of both type I and III interferons. Both interferons are translated and secreted from the infected cell in an autocrine or paracrine manner. Upon binding of type I IFN to the IFNAR1/IFNAR2 and of type III IFN to the IFNLR1/IL-10R2 receptor, signal transductions are initiated leading to the formation of the ISGF3 complex (IRF9/p-STAT1/p-STAT2) which then acts as a transcription factor driving the expression of interferon stimulated genes.
Figure 2
Figure 2
Regulation of interferon-mediated receptor signaling. Table summarizing the current state of the knowledge of both interferon receptor tropism, binding affinity for interferons, internalization/recycling mechanism and their known regulation.
Figure 3
Figure 3
Signal transduction downstream type I and III interferon. Upon binding of type I IFN to the IFNAR1/IFNAR2 and of type III IFN to the IFNLR1/IL-10R2 receptor transactivation of JAK1 and TYK2 leads to the phosphorylation of STATs. Upon phosphorylation STAT molecules form three main complexes 1) STAT5/CrkL, 2) STAT homo- or heterodimers and 3) the ISGF3 complex (IRF9/p-STAT1/p-STAT2). All of these complexes act as transcription factors driving the production of interferon stimulated genes through the binding of specific motifs in their promoter sequences: GAS and ISRE elements.

Similar articles

See all similar articles

Cited by 3 articles

References

    1. Isaacs A., Lindenmann J. Virus interference. I. The interferon. Proc. R. Soc. Lond. Ser. B Biol. Sci. 1957;147:258–267. - PubMed
    1. Hoffmann H.H., Schneider W.M., Rice C.M. Interferons and viruses: An evolutionary arms race of molecular interactions. Trends Immunol. 2015;36:124–138. doi: 10.1016/j.it.2015.01.004. - DOI - PMC - PubMed
    1. Pestka S., Krause C.D., Sarkar D., Walter M.R., Shi Y., Fisher P.B. Interleukin-10 and related cytokines and receptors. Annu. Rev. Immunol. 2004;22:929–979. doi: 10.1146/annurev.immunol.22.012703.104622. - DOI - PubMed
    1. Langer J.A., Cutrone E.C., Kotenko S. The Class II cytokine receptor (CRF2) family: Overview and patterns of receptor-ligand interactions. Cytokine Growth Factor Rev. 2004;15:33–48. doi: 10.1016/j.cytogfr.2003.10.001. - DOI - PubMed
    1. LaFleur D.W., Nardelli B., Tsareva T., Mather D., Feng P., Semenuk M., Taylor K., Buergin M., Chinchilla D., Roshke V., et al. Interferon-κ, a Novel Type I Interferon Expressed in Human Keratinocytes. J. Biol. Chem. 2001;276:39765–39771. doi: 10.1074/jbc.M102502200. - DOI - PubMed
Feedback