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.
Highlights
Six years ago Isaacs and Lindemann made an amazing discovery when they described molecules able to “interfere” with influenza virus replication [1]
Other non-canonical forms of ISGF3 have been reported: the ISGF3II complex including phosphorylated STAT1, unphosporylated STAT2 and IRF9, and the ISGF3-like complex formed by STAT2 and IRF9 have been shown to be assembled mainly upon type I and II IFN treatment leading to prolonged interferon stimulated genes (ISGs) induction [117,131,132,133,134]
Members of the interferon regulatory factor (IRF) family (e.g., IRF-1) are transcriptionally upregulated upon IFN stimulation of cells. These transcription factors, in turn induce the transcription of a subset of ISGs by binding to specific promoter regions (IRF-E sites) which overlap with the interferon sensitive response elements (ISRE) sequence [159,160,161,162]
Summary
Six years ago Isaacs and Lindemann made an amazing discovery when they described molecules able to “interfere” with influenza virus replication [1]. Type I and III IFNs are non-related from both sequence and structure perspective as well as using two different receptor complexes for their signaling, both cytokines induce a remarkably similar panel of interferon stimulated genes (ISGs). This observation led to the hypothesis that both cytokines were functionally redundant [29,30,31,32,33,34]. This review will focus on the differences emanating from receptor activation to the regulations of ISG induction following either type I or III IFN stimulation
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