The interferons and their receptors—distribution and regulation

Abstract

The interferons (IFNs) were originally described over 50 years ago, identified by their ability to confer viral resistance to cells. We now know that they are much more than just anti-viral cytokines collectively having roles in both innate and adaptive immune responses, in tumor surveillance and defense, and modulation of immune cell function. Three types of IFN have now been described, simply referred to as type I, II and III. Distinguishable by the unique receptors that they rely on for signal transduction, the three types of IFN have specific and varied roles in the maintenance of human health and defense against pathogens. In mounting an IFN-mediated immune response, the human body has developed the ability to regulate IFN-mediated signal transduction. Like all cytokines, the ability of a cell to respond to IFN is completely dependent on the presence of its cognate receptor on the surface of the target cell. Thus, one of the major mechanisms used by the human body to regulate the strength and duration of the IFN response is through regulation of receptor levels, thereby altering the cytokine-specific responsiveness of the target cell. This review will discuss the receptor system utilized by the type I IFNs and compare it with that of the type II and III IFNs, which also regulate immune responses through controlling receptor level on the cell surface. Keywords: interferon signaling; receptors; regulation Discovered over 50 years ago, the interferons (IFNs) were first identified and are historically best known for their ability to elicit viral resistance to cells. 1 On the basis of this criteria the IFNs were initially classified into two types-the type I family composed of the acid-stable forms IFNa and IFNb, whereas the acid-labile form, IFNg, was classified as the lone type II IFN. 2 In recent years, a third type of IFN has been described, IFNl. 3 Originally termed interleukin (IL)-28a/b and IL-29 these proteins have been re-classified as IFNs based on the similar modes of induction and anti-viral activities they share with the type I and type II IFNs. 3 However, although the type I and type III IFNs are induced during a viral infection and are, at least in part, involved in host defense against viruses, the type II IFN is primarily involved in the allergic response, in host defense against intracellular pathogens and in control of tumors.The cytokines that make up the three types of IFNs share basic secondary structural elements with an overall five helical bundle architecture. The IFNs are all classified as class II alpha-helical cytokines and thus in the same protein family as IL-10, But besides a conserved overall helical-bundle fold, the IFNs otherwise share very limited homology, undoubtedly reflected by their use of distinct receptors for signal transduction. There are nine identified mammalian type I IFN subtypes including IFN-a, of which there are 13 known subtypes, and single forms of IFN-b, IFN-e, IFN-k, IFN-o, IFN-d, IFN-t, IFN-v, IFN -z. 4 These cytokines can share as much as 100% homology ...

Fine-tuning type I IFN signaling: A new chapter in the IFN saga

“…Chen et al [5] found that IFN-α-induced STAT1 phosphorylation, STAT1 nuclear localization and induction of a STAT1 target gene, ISG15 (IFN-stimulated gene 15), were all diminished in SETD2-deficient HepG2 cell lines (SETD2-KO cells) and primary hepatocytes from Setd2 conditional KO mice. Impaired STAT1 activation was also observed when SETD2-KO cells were stimulated by other types of IFN, namely, IFN-γ and IFN-λ, indicating there is a shared SETD2-mediated regulation of STAT1 downstream of the three distinct classes of IFN receptors [6]. In contrast, overexpression of the SETD2 SET domain (SETD2-F2) in SETD2-KO cells restored IFN-α-induced ISG15 mRNA expression, indicating the critical role of the SET domain.…”

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

“…In humans, type I IFNs comprise several IFNa subtypes and single isoforms of IFNb, -", -k and -! (de Weerd & Nguyen, 2012;Stetson & Medzhitov, 2006). A more recently described group of IFNs is the type III IFNs, also called the IFNls.…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…The type I IFNs are by far the largest family and consist of .20 individual members, such as IFN-a, -b, -«, -k, and -d (2). These cytokines bind to cell surface IFN-a receptor (IFNAR) that is composed of two subunits: IFNAR1 and IFNAR2 (3,4). Type I IFNs are produced in large quantities following viral infection and are regarded as the archetypal antiviral cytokine.…”

“…3,33). This receptor engagement induces phosphorylation of the intracellular receptor-associated JAK kinases JAK1 and TYK2, which leads to phosphorylation, dimerization, and nuclear translocation of STAT transcription factors.…”