Interferon gamma

Interferon, gamma
Line representation of the crystallographic structure of interferon gamma.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1EKU, 1FG9, 1FYH, 1HIG, 3BES
Identifiers
Symbols	IFNG ; IFG; IFI
External IDs	OMIM: 147570 MGI: 107656 HomoloGene: 55526 GeneCards: IFNG Gene
Gene ontology Molecular function • cytokine activity • interferon-gamma receptor binding Cellular component • extracellular region • extracellular space • intracellular • external side of plasma membrane Biological process • protein import into nucleus, translocation • negative regulation of transcription from RNA polymerase II promoter • neutrophil apoptotic process • regulation of the force of heart contraction • adaptive immune response • CD8-positive, alpha-beta T cell differentiation involved in immune response • apoptotic process • movement of cell or subcellular component • humoral immune response • cell cycle arrest • cell surface receptor signaling pathway • positive regulation of cell proliferation • response to virus • positive regulation of gene expression • negative regulation of gene expression • positive regulation of epithelial cell migration • cytokine-mediated signaling pathway • antigen processing and presentation • neutrophil chemotaxis • negative regulation of epithelial cell differentiation • endoplasmic reticulum unfolded protein response • negative regulation of myelination • positive regulation of synaptic transmission, cholinergic • negative regulation of interleukin-17 production • positive regulation of interleukin-12 production • positive regulation of interleukin-23 production • positive regulation of tumor necrosis factor production • positive regulation of peptidyl-serine phosphorylation of STAT protein • positive regulation of smooth muscle cell apoptotic process • positive regulation of T cell proliferation • response to drug • positive regulation of tyrosine phosphorylation of Stat1 protein • defense response to bacterium • defense response to protozoan • negative regulation of growth of symbiont in host • positive regulation of chemokine biosynthetic process • positive regulation of interleukin-12 biosynthetic process • positive regulation of MHC class II biosynthetic process • positive regulation of interleukin-6 biosynthetic process • positive regulation of nitric oxide biosynthetic process • positive regulation of neuron differentiation • positive regulation of osteoclast differentiation • positive regulation of transcription from RNA polymerase II promoter • positive regulation of isotype switching to IgG isotypes • negative regulation of smooth muscle cell proliferation • positive regulation of interleukin-1 beta secretion • regulation of insulin secretion • sensory perception of mechanical stimulus • positive regulation of membrane protein ectodomain proteolysis • defense response to virus • positive regulation of killing of cells of other organism • interferon-gamma-mediated signaling pathway • regulation of interferon-gamma-mediated signaling pathway • positive regulation of fructose 1,6-bisphosphate 1-phosphatase activity • positive regulation of fructose 1,6-bisphosphate metabolic process • positive regulation of vitamin D biosynthetic process • positive regulation of calcidiol 1-monooxygenase activity • cellular response to lipopolysaccharide • cellular response to interleukin-18 • extrinsic apoptotic signaling pathway • regulation of neuronal action potential • positive regulation of tumor necrosis factor (ligand) superfamily member 11 production • regulation of hepatocyte proliferation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3458	15978
Ensembl	ENSG00000111537	ENSMUSG00000055170
UniProt	P01579	P01580
RefSeq (mRNA)	NM_000619	NM_008337
RefSeq (protein)	NP_000610	NP_032363
Location (UCSC)	Chr 12: 68.15 – 68.16 Mb	Chr 10: 118.44 – 118.45 Mb
PubMed search	[1]	[2]

Interferon gamma
Crystal structure of a biologically active single chain mutant of human interferon gamma
Identifiers
Symbol	IFN gamma
Pfam	PF00714
Pfam clan	CL0053
InterPro	IPR002069
SCOP	1rfb
SUPERFAMILY	1rfb
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Interferon gamma

Systematic (IUPAC) name
Human interferon gamma-1b
Clinical data
Trade names	Actimmune
AHFS/Drugs.com	monograph
MedlinePlus	a601152
Identifiers
CAS Number	82115-62-6 Y 98059-61-1
ATC code	L03AB03 (WHO)
DrugBank	DB00033 N
ChEMBL	CHEMBL1201564 N
Chemical data
Formula	C761H1206N214O225S6
Molecular mass	17145.6 g/mol
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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 IFNG gene.

Function

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.

Structure

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.

Receptor binding

Figure 3. IFN dimer interacting with two IFNGR1 receptor molecules.

See also: Interferon-gamma receptor

Cellular responses to IFNγ are activated through its interaction with a heterodimeric receptor consisting of Interferon gamma receptor 1 (IFNGR1) and Interferon gamma receptor 2 (IFNGR2). IFNγ binding to the receptor activates the JAK-STAT pathway. IFNγ 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 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 proteolytic cleavage.

Biological activity

IFNγ is secreted by T helper cells (specifically, T_h1 cells), cytotoxic T cells (T_C cells) and NK cells only. 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 NK cell activity
• Increase antigen presentation and lysosome activity of macrophages.
• Activate inducible Nitric Oxide Synthase iNOS
• Induces the production of IgG2a and IgG3 from activated plasma B cells
• Promotes T_h1 differentiation by upregulating the 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 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 T_h1 cells: T_h1 cells secrete IFNγ, which in turn causes more undifferentiated CD4⁺ cells (Th0 cells) to differentiate into T_h1 cells, representing a positive feedback loop—while suppressing T_h2 cell differentiation. (Equivalent defining cytokines for other cells include IL-4 for T_h2 cells and IL-17 for Th17 cells.)

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

Activity in granuloma formation

A 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 tuberculosis, leprosy, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and cat scratch disease. Examples of non-infectious granulomatous diseases are sarcoidosis, Crohn's disease, berylliosis, giant-cell arteritis, granulomatosis with polyangiitis, Churg–Strauss syndrome, pulmonary 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 T_h1 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 INFγ-induced granuloma formation are activation of T_h1 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 T_h1 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 T_h1 helper cells with further release of IFNγ. Finally, macrophages surround the T_h1 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.

Therapeutic use

Interferon-γ 1b is approved by the U.S. Food and Drug Administration to treat chronic granulomatous disease and 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 Children’s Hospital of Philadelphia for the treatment of Friedreich's ataxia.

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

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

Interactions

Interferon-γ has been shown to interact 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 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.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.