Interferon (IFN) Overview
Following viral infection, the human body triggers a complex regulatory system of innate and adaptive immune responses designed to defend against these foreign invaders. One of the many responses to the viral invasion is the induction of a family of pleiotropic cytokines known as Interferons (IFN)1. Induction of interferon (IFN) gene expression leads to increase cellular resistance to viral infection and may also affect cell growth. Two subtypes of interferons comprise the IFN family of cytokines. Over 20 type I interferons, which include IFNα and IFNβ, have been identified and share the ability to bind to Type I IFN (IFNAR) receptors. IFNγ constitutes the only Type II Interferon and binds to the IFNγ-receptor (IFNGR)2. Activation of the Toll-like receptor pathway following viral infection leads to the increased production of IFNα and IFNβ and the further induction of adaptive immune responses by increasing MHC-I (Major Histocompatibility Complex Class-I).
IFN-Receptors, both Type I and Type II are composted of at least two distinct subunits. (IFNR1 and IFNR2 for the Type-I IFN receptor, and IFN-γR1 and IFN-γR2 for the Type-II IFN receptor). To mediate signaling, subunits of the IFN receptors are associated with a member of the JAK (Janus Activated Kinase) family. The IFNR1 subunit of the Type I IFN receptor is associated with TYK2 (Tyrosine Kinase-2),and IFNR2 is associated with JAK13,4,5. The IFN-γR1 subunit of the Type I IFN receptor is associated with JAK1,whereas IFN-γR2 is associated with JAK24.Activation of both Type I and Type II receptors following ligand binding results in dimerization and rearrangement of receptor subunits leading to the activation of associated JAKs by autophosphorylation and the further activation of STAT proteins (STAT1, STAT2, STAT3, and STAT5). Following phosphorylation, activated STAT form homodimers, then translocate to the nucleus where they initiate transcription of IFN-stimulated genes4. Type I interferons can also induce the formation of the ISGF3 complex, composed of STAT1, STAT2, and IRF9, An important transcriptional complex that is induced by Type-I IFNs is the ISGF3 (ISG Factor-3) Complex6,7. The ISGF3 complexes bind ISRE (IFN-Stimulated Response Elements) further inducing the transcription of IFN-stimulated genes which contain ISREs within their promoters. IFNγ binding to the IFNγ-receptor leads to the downstream tyrosine phosphorylation of STAT1 at residue Tyr701. The resulting Tyr701-phosphoryled STAT1 homodimers translocated to the nucleus and bind to GAS6. The tyrosine phosphorylated form of STAT1 forms homodimers that translocate to the nucleus and bind GAS (IFNγ-Activated Sites) elements to induce expression of IFNγ-regulated genes.
The Mitogen Activated Protein Kinase (MAPK) pathway has also been shown to be regulated by interferon signaling8. Activated JAKs phosphorylate Vav, a guanine nucleotide exchange factor, resulting in the downstream activation of Rac1. Activated Rac1 further activates MEKK1 (MAP3K1), leading to the phosphorylation of MEK3 (MAP2K3) and MEK6 (MAP2K6) which in turn regulates p38MAPK (MAPK14) phosphorylation. Activated p38 subsequently regulates activation of multiple downstream effectors, including the mitogen- and stress-activated kinases MSK1 and MSK2. The specific transcription factors that are regulated by p38s include CREB (cAMP Responsive Element Binding protein) and Histone-H3. Activated TYK2 and JAK1 regulate tyrosine phosphorylation of IRS1 and IRS2 (Insulin Receptor Substrate),which provide docking sites for the SH2 (SRC Homology-2) domains of the regulatory subunit (p85) of PI3K (Phosphatidylinositol 3-Kinase). PI3K further activates mTOR (Mammalian Target of Rapamycin), a critical regulator of translational proteins.
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