Interferon gamma

Interferon gamma (IFNγ) is a dimerized soluble is_associated_with::cytokine that is the only member of the type II class of is_associated_with::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 IFNG is_associated_with::gene.

Function
IFNγ, or type II interferon, is a cytokine that is critical for innate and is_associated_with::adaptive immunity against viral, some bacterial and protozoal infections. IFNγ is an important activator of macrophages and inducer of Class I major histocompatibility complex (MHC) molecule expression. Aberrant IFNγ expression is associated with a number of autoinflammatory and is_associated_with::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 is_associated_with::CD4 Th1 and is_associated_with::CD8 cytotoxic T lymphocyte (CTL) effector T cells once is_associated_with::antigen-specific immunity develops.

Structure
The IFNγ is_associated_with::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.

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.

Receptor binding
Cellular responses to IFNγ are activated through its interaction with a heterodimeric receptor consisting of is_associated_with::Interferon gamma receptor 1 (IFNGR1) and is_associated_with::Interferon gamma receptor 2 (IFNGR2). IFNγ binding to the receptor activates the is_associated_with::JAK-STAT pathway. IFNγ also binds to the is_associated_with::glycosaminoglycan is_associated_with::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 IFNγ to HS inhibits its biological activity.

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 is_associated_with::proteolytic cleavage.

Biological activity
It was believed earlier that IFNγ is secreted by is_associated_with::T helper cells (specifically, Th1 cells), is_associated_with::cytotoxic T cells (TC cells) and is_associated_with::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 is_associated_with::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 is_associated_with::NK cell activity
 * Increase antigen presentation and is_associated_with::lysosome activity of is_associated_with::macrophages.
 * Activate inducible Nitric Oxide Synthase is_associated_with::iNOS
 * Induces the production of is_associated_with::IgG2a and is_associated_with::IgG3 from activated plasma is_associated_with::B cells
 * Promotes Th1 differentiation by upregulating the is_associated_with::transcription factor T-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 is_associated_with::class I MHC molecules as well as is_associated_with::class II MHC on antigen-presenting cells&mdash;to be specific, through induction of is_associated_with::antigen processing genes, including subunits of the is_associated_with::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 is_associated_with::leukocyte migration
 * Induces the expression of intrinsic defense factors&mdash;for example, with respect to is_associated_with::retroviruses, relevant genes include is_associated_with::TRIM5alpha, is_associated_with::APOBEC, and is_associated_with::Tetherin, representing directly antiviral effects

IFNγ is the primary is_associated_with::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 is_associated_with::positive feedback loop&mdash;while suppressing Th2 cell differentiation. (Equivalent defining cytokines for other cells include IL-4 for Th2 cells and IL-17 for Th17 cells.)

is_associated_with::NK cells and is_associated_with::CD8+ cytotoxic T cells also produce IFNγ. IFNγ suppresses is_associated_with::osteoclast formation by rapidly degrading the is_associated_with::RANK adaptor protein is_associated_with::TRAF6 in the is_associated_with::RANK-is_associated_with::RANKL signaling pathway, which otherwise stimulates the production of is_associated_with::NF-κB.

Activity in granuloma formation
A is_associated_with::granuloma is the body's way of dealing with a substance it cannot remove or sterilize. Infectious causes of granulomas (infections are typically the most common cause of granulomas) include is_associated_with::tuberculosis, is_associated_with::leprosy, is_associated_with::histoplasmosis, is_associated_with::cryptococcosis, is_associated_with::coccidioidomycosis, is_associated_with::blastomycosis, and is_associated_with::cat scratch disease. Examples of non-infectious granulomatous diseases are is_associated_with::sarcoidosis, is_associated_with::Crohn's disease, is_associated_with::berylliosis, is_associated_with::giant-cell arteritis, is_associated_with::granulomatosis with polyangiitis, is_associated_with::Churg–Strauss syndrome, pulmonary is_associated_with::rheumatoid nodules, and aspiration of food and other particulate material into the lung. The infectious pathophysiology of granulomas is discussed primarily here.

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 is_associated_with::mycobacterial infections allows the macrophages to overcome the inhibition of is_associated_with::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 is_associated_with::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 is_associated_with::decidual arteries. These models display abnormally low amounts of cells or is_associated_with::necrosis of decidua.

Therapeutic use
Interferon-γ 1b is approved by the U.S. Food and Drug Administration to treat is_associated_with::chronic granulomatous disease and is_associated_with::osteopetrosis.

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.

It is being studied at the is_associated_with::Children’s Hospital of Philadelphia for the treatment of is_associated_with::Friedreich's ataxia.

Although not officially approved, Interferon-γ has also been shown to be effective in treating patients with moderate to severe is_associated_with::atopic dermatitis.

It is manufactured by InterMune as Actimmune and costs around USD300 per vial.

Interactions
Interferon-γ has been shown to interact with is_associated_with::Interferon gamma receptor 1.

Regulation
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 is_associated_with::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.