Interferon gamma (IFNγ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes  or tuberculin-sensitized mouse peritoneal lymphocytes challenged with PPD; the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed interferon gamma release assay used to test for tuberculosis. In humans, the IFNγ protein is encoded by the IFNGgene.
IFNγ, or type II interferon, is a cytokine that is critical for innate and adaptive immunity against viral, some bacterial and protozoal infections. IFNγ is an important activator of macrophages and inducer of Class II major histocompatibility complex (MHC) molecule expression. Aberrant IFNγ expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFNγ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects. IFNγ is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 Th1 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops.
The IFNγ 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.
Figure 1. Line and cartoon representation of an IFNγ 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.
Figure 2. Line and cartoon representation of an IFNγ dimer.
Figure 3. IFN dimer interacting with two IFNGR1 receptor molecules.
The structural models shown in figures 1-3 for IFNγ are all shortened at their C-termini by 17 amino acids. Full length IFNγ is 143 amino acids long, the models are 126 amino acids long. 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 IFNγ-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 IFNγ is unclear, however binding of the D1 cluster to HS may protect it from proteolytic cleavage.
It was believed earlier that IFNγ is secreted by T helper cells (specifically, Th1 cells), cytotoxic T cells (TC cells) and NK cells only. But later studies showed that myeloid cells, dendritic cells and macrophages in particular, also secrete IFNγ that is likely important for cell self activation during the onset of the infection. Also, IFNγ is the only Type II interferon, and it is serologically distinct from Type I interferons: it is acid-labile, while the type I variants are acid-stable.
IFNγ has antiviral, immunoregulatory, and anti-tumor properties. It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are:
Promotes Th1 differentiation by upregulating the transcription factorT-bet, ultimately leading to cellular immunity: cytotoxic CD8+ T-cells and macrophage activity - while suppressing Th2 differentiation, which would cause a humoral (antibody) response
Cause normal cells to increase expression of class I MHC molecules as well as class II MHC on antigen-presenting cells—to be specific, through induction of antigen processing genes, including subunits of the immunoproteasome (MECL1, LMP2, LMP7), as well as TAP and ERAAP in addition possibly to the direct upregulation of MHC heavy chains and B2-microglobulin itself
Promotes adhesion and binding required for leukocyte migration
Induces the expression of intrinsic defense factors—for example, with respect to retroviruses, relevant genes include TRIM5alpha, APOBEC, and Tetherin, representing directly antiviral effects
IFNγ is the primary cytokine that defines Th1 cells: Th1 cells secrete IFNγ, which in turn causes more undifferentiated CD4+ cells (Th0 cells) to differentiate into Th1 cells, representing a positive feedback loop—while suppressing Th2 cell differentiation. (Equivalent defining cytokines for other cells include IL-4 for Th2 cells and IL-17 for Th17 cells.)
The key association between IFNγ and granulomas is that IFNγ activates macrophages so that they become more powerful in killing intracellular organisms. Activation of macrophages by IFNγ from Th1 helper cells in mycobacterial infections allows the macrophages to overcome the inhibition of phagolysosome maturation caused by mycobacteria (to stay alive inside macrophages). The first steps in interferon-γ-induced granuloma formation are activation of Th1 helper cells by macrophages releasing IL-1 and IL-12 in the presence of intracellular pathogens, and presentation of antigens from those pathogens. Next the Th1 helper cells aggregate around the macrophages and release IFNγ, which activates the macrophages. Further activation of macrophages causes a cycle of further killing of intracellular bacteria, and further presentation of antigens to Th1 helper cells with further release of IFNγ. Finally, macrophages surround the Th1 helper cells and become fibroblast-like cells walling off the infection.
Activity during pregnancy
Uterine Natural Killer cells (NK) secrete high levels of chemoattractants, such as IFNγ. IFNγ dilates and thins the walls of maternal spiral arteries to enhance blood flow to the implantation site. This remodeling aids in the development of the placenta as it invades the uterus in its quest for nutrients. IFNγ knockout mice fail to initiate normal pregnancy-induced modification of decidual arteries. These models display abnormally low amounts of cells or necrosis of decidua.
It was not approved to treat idiopathic pulmonary fibrosis (IPF). In 2002, the manufacturer InterMune issued a press release saying that phase III data demonstrated survival benefit in IPF and reduced mortality by 70% in patients with mild to moderate disease. The U.S. Department of Justice charged that the release contained false and misleading statements. InterMune's chief executive, Scott Harkonen, was accused of manipulating the trial data, was convicted in 2009 of wire fraud, and was sentenced to fines and community service. Harkonen appealed his conviction to the U.S. Court of Appeals for the Ninth Circuit, and lost.
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-29. Furthermore, there is evidence that interferon-gamma expression is regulated via GAPDH in T-cells. This interaction takes place in the 3'UTR, where binding of GAPDH prevents the translation of the mRNA sequence.
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