Introduction of Type II Interferon

Type II interferon Unlike the type I IFNs, which all appear to signal as monomeric cytokines, IFNγ signals as an anti-parellel homodimer. The complex through which this cytokine signals is composed of four transmembrane-spanning receptors; two chains of each of the high-affinity(IFNGR1) and low-affinity receptors (IFNGR2). The IFNγ homodimer engages directly with the two IFNGR1 chains on opposing sides of the cytokine dimer. IFNGR1 has been shown to be pre-associated with IFNGR2 and although the ligand does not engage IFNGR2 directly, ligand-induced conformational changes in both receptors have been reported. Despite the fact that both IFNGR1 and IFNGR2 are not always present together on the surface of all cells, both receptor components are required for full activity of IFNγ. For signal transduction via the JAK/STAT pathway, IFNGR1 binds to JAK1 whereas IFNGR2 binds to JAK2. Although both kinases are necessary for signal transduction, only JAK1 has been demonstrated to be required for the formation of the full IFNγ signaling complex.

Introduction of Type I Interferon

Type I interferons are a large group of structurally similar cytokines, in humans including more than 13 different members of IFNα as well as IFNβ, IFNε, IFNκ and IFNω. The genes encoding type I interferons are clustered in one locus on the same chromosome (chromosome 9 in humans and chromosome 4 in mice), and they have been suggested to have diverged from a common ancestor, with the IFNβ gene being the primordial gene. Despite their seemingly broad range of amino-acid homologies, all type I IFNs signal through a common heterodimeric receptor composed of low- (IFNAR1) and high-affinity (IFNAR2) receptor components.

More than 50 years after their discovery, type I interferons have been included in our therapeutic armamentarium and are indicated for several disease entities. Firstly, type I interferons are widely used for the treatment of chronic viral infections, mainly by hepatitis B virus and hepatitis C virus. Type I interferons have also been used in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), with more success in animal models than in the clinic. In addition to the above-described beneficial effects in infections, in malignancies and in some autoimmune/inflammatory diseases, there is evidence that type I interferons can also be detrimental for the host by promoting autoimmunity, inflammation and interferon treatment-related toxicities in a context-dependent manner.

Overview of Interferons

In studying the phenomenon of viral interference, Isaacs and Lindenmann discovered interferon in 1957. On the basis of this criteria the IFNs were initially classified into two types—the type I family composed of the acid-stable forms IFNα and IFNβ, whereas the acid-labile form, IFNγ, was classified as the lone type II IFN.2 In recent years, a third type of IFN has been described, IFNλ. 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. 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.

Ligand types	Names	Receptor chain 1	Receptor chain 2
Type I IFN	IFN-αIFN-βIFN-εIFN-κ IFN-ω IFN-υ	IFN-αR1(Also IFN-αRα, IFNAR1)	IFN-αR2(Also IFN-αRβ,IFNAR2)
Type II IFN	IFN-γ	IFN-γR1(Also IFN-γRα, IFNGR1)	IFN-γR2(Also IFN-γRβ,IFNGR2)
Type III IFN	IL-28AIL-28BIL-29	IL-28R1	IL-10R2

Introduction of Type III Interferon

Similar to the type I IFNs, the type III IFNs signal as monomeric cytokines engaging one copy of each of their low-affinity and high affinity receptors. However, unlike both the type I and type II IFNs, which employ their own dedicated receptors, the IFNλs utilize one unique receptor (IFNLR1) but also one required for signal transduction by IL-10, IL-22 and IL-26 (IL10RB). The receptor-associated JAK kinases, JAK1 with IFNLR1 and Tyk2 with IL10RB are responsible for activation of the JAK/STAT pathway upon IFNl engagement of this receptor complex. As IL10RB is also common to the signaling complexes for IL-10, IL-22 and IL-26, it remains to be seen whether there is any functional cross-talk between the type III IFNs and these cytokines as a result of having a shared receptor.

Contact Us