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Interferon-gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs. In humans, the IFN-γ protein is encoded by the IFNG gene.
IFN-γ, or type II interferon, is a cytokine that is critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. Aberrant IFN-γ expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFN-γ in the immune system stems in part from its ability to inhibit viral replication directly, but, most important, derives from its immunostimulatory and immunomodulatory effects. IFN-γ is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops.
The IFN-γ monomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region. This is shown in the structural models below. The α-helices in the core of the structure are numbered 1 to 6.
Line and cartoon representation of a IFN-γ monomer.
The biologically active dimer is formed by anti-parallel inter-locking of the two monomers as shown below. In the cartoon model, one monomer is shown in red, the other in blue.
Line and cartoon representation of a IFN-γ dimer.
IFN dimer interacting with two IFNGR1
Cellular responses to IFN-γ are activated through its interaction with a heterodimeric receptor consisting of Interferon gamma receptor 1 (IFNGR1) and Interferon gamma receptor 2 (IFNGR2). IFN-γ binding to the receptor activates the JAK-STAT pathway. IFN-γ also binds to the glycosaminoglycan heparan sulfate (HS) at the cell surface. However, in contrast to many other heparan sulfate binding proteins, where binding promotes biological activity, the binding of IFN-γ to HS inhibits its biological activity.
The structural models shown in figures 1-3 for IFN-γ are all shortened at their C-termini by 17 amino acids. Full length IFN-γ is 143 amino acids in length, the models are 126 amino acids in length. Affinity for heparan sulfate resides solely within the deleted sequence of 17 amino acids. Within this sequence of 17 amino acids lie two clusters of basic amino acids termed D1 and D2, respectively. Heparan sulfate interacts with both of these clusters. In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFN-γ-receptor complexes form. Interactions between the D1 cluster of amino acids and the receptor may be the first step in complex formation. By binding to D1 HS may compete with the receptor and prevent active receptor complexes from forming.
The biological significance of heparan sulfates interaction with IFN-γ is unclear, however binding of the D1 cluster to HS may protect it from proteolytic cleavage.
In contrast to interferon-α and interferon-β, which can be expressed by all cells, IFN-γ is secreted by Th1 cells, Tc cells, dendritic cells and NK cells. Also known as immune interferon, IFN-γ is the only Type II interferon. It is serologically distinct from Type I interferons and it is acid-labile, while the type I variants are acid-stable.
IFN-γ has antiviral, immunoregulatory, and anti-tumor properties. It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Amongst the effects are:
IFN-γ is the hallmark cytokine of Th1 cells (whereas Th2 cells produce IL-4 and Th17 cells produce IL-17). NK cells and CD8+ cytotoxic T cells also produce IFN-γ. IFN-γ suppresses osteoclast formation by rapidly degrading the RANK adaptor protein TRAF6 in the RANK-RANKL signaling pathway, which otherwise stimulates the production of NFκB.
Interferon gamma 1b is used to treat chronic granulomatous disease and osteopetrosis. It is manufactured by InterMune as Actimune® and costs around USD300 per vial.
Interferon-gamma has been shown to interact with Interferon gamma receptor 1.
There is evidence that interferon-gamma expression is regulated by a pseudoknotted element in its 5' UTR. There is also evidence that interferon-gamma is regulated either directly or indirectly by the microRNAs: miR-221, miR-155, miR-145 and miR-198.
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1eku: CRYSTAL STRUCTURE OF A BIOLOGICALLY ACTIVE SINGLE CHAIN MUTANT OF HUMAN IFN-GAMMA
1fg9: 3:1 COMPLEX OF INTERFERON-GAMMA RECEPTOR WITH INTERFERON-GAMMA DIMER
1fyh: 1:1 COMPLEX BETWEEN AN INTERFERON GAMMA SINGLE-CHAIN VARIANT AND ITS RECEPTOR
This article incorporates text from the United States National Library of Medicine, which is in the public domain.