Interferon gamma

Interferon gamma (IFNγ) is a dimerized soluble cytokine that is the only member of the type II class of interferons.[5] 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.[6] It was also shown to be produced in human lymphocytes.[7] or tuberculin-sensitized mouse peritoneal lymphocytes[8] 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.[9][10]

IFNG
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1EKU, 1FG9, 1FYH, 1HIG, 3BES
Identifiers
Aliases	IFNG, IFG, IFI, interferon, gamma, interferon gamma
External IDs	OMIM: 147570 MGI: 107656 HomoloGene: 55526 GeneCards: IFNG
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q15 Start 68,154,768 bp[1] End 68,159,740 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 D2|10 66.75 cM Start 118,441,046 bp[2] End 118,445,892 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • interferon-gamma receptor binding • cytokine activity • GO:0001948 protein binding Cellular component • extracellular region • external side of plasma membrane • perikaryon • neuron projection • cytoplasm • extracellular • cell Biological process • apoptotic process • positive regulation of MHC class II biosynthetic process • negative regulation of smooth muscle cell proliferation • cellular response to interleukin-18 • movement of cell or subcellular component • antigen processing and presentation • positive regulation of fructose 1,6-bisphosphate 1-phosphatase activity • regulation of transcription, DNA-templated • positive regulation of tumor necrosis factor (ligand) superfamily member 11 production • positive regulation of interleukin-12 production • positive regulation of autophagy • positive regulation of smooth muscle cell apoptotic process • positive regulation of chemokine biosynthetic process • regulation of insulin secretion • extrinsic apoptotic signaling pathway • regulation of the force of heart contraction • regulation of neuronal action potential • positive regulation of nitric oxide biosynthetic process • positive regulation of synaptic transmission, cholinergic • response to virus • positive regulation of membrane protein ectodomain proteolysis • positive regulation of epithelial cell migration • positive regulation of osteoclast differentiation • positive regulation of killing of cells of other organism • positive regulation of calcidiol 1-monooxygenase activity • positive regulation of peptidyl-serine phosphorylation of STAT protein • negative regulation of transcription from RNA polymerase II promoter • positive regulation of vitamin D biosynthetic process • positive regulation of interleukin-6 biosynthetic process • neutrophil chemotaxis • negative regulation of gene expression • positive regulation of fructose 1,6-bisphosphate metabolic process • positive regulation of transcription, DNA-templated • endoplasmic reticulum unfolded protein response • positive regulation of interleukin-12 biosynthetic process • cell surface receptor signaling pathway • positive regulation of gene expression • regulation of interferon-gamma-mediated signaling pathway • defense response to bacterium • defense response to virus • positive regulation of interleukin-1 beta secretion • positive regulation of neuron differentiation • positive regulation of T cell proliferation • cell cycle arrest • positive regulation of cell proliferation • regulation of hepatocyte proliferation • immune response • regulation of immune response • positive regulation of tumor necrosis factor production • CD8-positive, alpha-beta T cell differentiation involved in immune response • neutrophil apoptotic process • sensory perception of mechanical stimulus • regulation of growth • positive regulation of isotype switching to IgG isotypes • positive regulation of exosomal secretion • positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation involved in immune response • negative regulation of interleukin-17 production • cellular response to lipopolysaccharide • T cell receptor signaling pathway • negative regulation of epithelial cell differentiation • negative regulation of myelination • inflammatory cell apoptotic process • positive regulation of interleukin-23 production • response to drug • positive regulation of transcription from RNA polymerase II promoter • negative regulation of cell proliferation • defense response to protozoan • positive regulation of cell adhesion • negative regulation of glomerular mesangial cell proliferation • negative regulation of fibroblast proliferation • regulation of glial cell proliferation • positive regulation of apoptotic process • positive regulation of protein phosphorylation • adaptive immune response • humoral immune response • regulation of protein ADP-ribosylation • positive regulation of protein complex assembly • positive regulation of tyrosine phosphorylation of STAT protein • negative regulation of transcription, DNA-templated • regulation of defense response to virus by host • interferon-gamma-mediated signaling pathway • positive regulation of protein serine/threonine kinase activity • positive regulation of protein deacetylation • positive regulation of core promoter binding • interleukin-12-mediated signaling pathway • regulation of regulatory T cell differentiation • positive regulation of protein localization to plasma membrane • regulation of receptor activity • positive regulation of protein import into nucleus • microglial cell activation • positive regulation of NMDA glutamate receptor activity • JAK-STAT cascade • positive regulation of receptor biosynthetic process • positive regulation of tumor necrosis factor biosynthetic process • positive regulation of glycolytic process • astrocyte activation • positive regulation of interleukin-1 beta biosynthetic process • positive regulation of phagocytosis • positive regulation of neurogenesis • positive regulation of nitrogen compound metabolic process • positive regulation of nitric-oxide synthase biosynthetic process • neuroinflammatory response • negative regulation of amyloid-beta clearance • positive regulation of neuron death • positive regulation of cellular respiration • positive regulation of amyloid-beta formation • negative regulation of tau-protein kinase activity • positive regulation of ferrous iron import across plasma membrane • positive regulation of tumor necrosis factor secretion Sources:Amigo / QuickGO
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	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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
SCOPe	1rfb / SUPFAM
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Interferon gamma

Clinical data
Trade names	Actimmune
AHFS/Drugs.com	Monograph
MedlinePlus	a601152
ATC code	L03AB03 (WHO)
Identifiers
IUPAC name Human interferon gamma-1b
CAS Number	98059-61-1^Y
DrugBank	DB00033^N
ChemSpider	none
UNII	21K6M2I7AG
ChEMBL	ChEMBL1201564^N
Chemical and physical data
Formula	C761H1206N214O225S6
Molar mass	17145.65 g·mol^−1
^NY (what is this?)  (verify)

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[11][12] as part of the adaptive immune response. IFNγ is also produced by non-cytotoxic innate lymphoid cells (ILC), a family of immune cells first discovered in the early 2010s.[13]

Structure

The IFNγ monomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region.[14][15] 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.[15]

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.[15]

Receptor binding

Figure 3. IFN dimer interacting with two IFNGR1 receptor molecules.[15]

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.[16]

The structural models shown in figures 1-3 for IFNγ[15] 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.[17] 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.[18] In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFNγ-receptor complexes form.[16] 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.[18]

Biological activity

IFNγ is secreted by T helper cells (specifically, T_h1 cells), cytotoxic T cells (T_C cells), macrophages, mucosal epithelial cells and NK cells. 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.[19] It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are:

• Promotes NK cell activity[20]
• Increases antigen presentation and lysosome activity of macrophages.
• Activates inducible nitric oxide synthase (iNOS)
• Induces the production of IgG2a and IgG3 from activated plasma B cells
• Causes 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
• Primes alveolar macrophages against secondary bacterial infections.[21][22]

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 toxoplasmosis. Examples of non-infectious granulomatous diseases are sarcoidosis, Crohn's disease, berylliosis, giant-cell arteritis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, 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).[20] The first steps in IFNγ-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.[23]

Production

Recombinant human interferon gamma, as an expensive biopharmaceutical, has been expressed in different expression systems including prokaryotic, protozoan, fungal (yeasts), plant, insect and mammalian cells. Human interferon gamma is commonly expressed in Escherichia coli, marketed as ACTIMMUNE®, however, the resulting product of the prokaryotic expression system is not glycosylated with a short half-life in the bloodstream after injection; the purification process from bacterial expression system is also very costly. Other expression systems like Pichia pastoris did not show satisfactory results in terms of yields.[24][25]

Therapeutic use

Interferon-γ 1b is approved by the U.S. Food and Drug Administration to treat chronic granulomatous disease[26] and osteopetrosis.[27]

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.[28]

It is being studied at the Children’s Hospital of Philadelphia for the treatment of Friedreich's ataxia.[29]

Although not officially approved, Interferon-γ has also been shown to be effective in treating patients with moderate to severe atopic dermatitis.[30][31][32]

Potential use in immunotherapy

Interferon gamma is not approved yet for the treatment in any cancer immunotherapy. However, improved survival was observed when Interferon gamma was administrated to patients with bladder carcinoma and melanoma cancers. The most promising result was achieved in patients with stage 2 and 3 of ovarian carcinoma. On the contrary, it was stressed: "Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth."[33] The in vitro study of IFN-gamma in cancer cells is more extensive and results indicate anti-proliferative activity of IFN-gamma leading to the growth inhibition or cell death, generally induced by apoptosis but sometimes by autophagy.[24] In addition, it has been reported that mammalian glycosylation of recombinant human interferon gamma, expressed in HEK293, improves its therapeutic efficacy compared to the unglycosylated form that is expressed in E. coli.[34]

Interactions

Interferon-γ has been shown to interact with Interferon gamma receptor 1.[35][36]

Diseases

Interferon-γ has been shown to be a crucial player in the immune response against some intracellular pathogens, including that of Chagas disease.[37] It has also been identified as having a role in seborrheic dermatitis.[38]

Regulation

There is evidence that interferon-gamma expression is regulated by a pseudoknotted element in its 5' UTR.[39] There is also evidence that interferon-gamma is regulated either directly or indirectly by the microRNAs: miR-29.[40] 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.[41]

References

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22. Yao Y, Jeyanathan M, Haddadi S, Barra NG, Vaseghi-Shanjani M, Damjanovic D, et al. (November 2018). "Induction of Autonomous Memory Alveolar Macrophages Requires T Cell Help and Is Critical to Trained Immunity". Cell. 175 (6): 1634–1650.e17. doi:10.1016/j.cell.2018.09.042. PMID 30433869.
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24. Razaghi A, Owens L, Heimann K (December 2016). "Review of the recombinant human interferon gamma as an immunotherapeutic: Impacts of production platforms and glycosylation". Journal of Biotechnology. 240: 48–60. doi:10.1016/j.jbiotec.2016.10.022. PMID 27794496.
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26. Todd PA, Goa KL (January 1992). "Interferon gamma-1b. A review of its pharmacology and therapeutic potential in chronic granulomatous disease". Drugs. 43 (1): 111–22. doi:10.2165/00003495-199243010-00008. PMID 1372855.
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29. Seyer L, Greeley N, Foerster D, Strawser C, Gelbard S, Dong Y, et al. (July 2015). "Open-label pilot study of interferon gamma-1b in Friedreich ataxia". Acta Neurologica Scandinavica. 132 (1): 7–15. doi:10.1111/ane.12337. PMID 25335475.
30. Akhavan A, Rudikoff D (June 2008). "Atopic dermatitis: systemic immunosuppressive therapy". Seminars in Cutaneous Medicine and Surgery. 27 (2): 151–5. doi:10.1016/j.sder.2008.04.004. PMID 18620137.
31. Schneider LC, Baz Z, Zarcone C, Zurakowski D (March 1998). "Long-term therapy with recombinant interferon-gamma (rIFN-gamma) for atopic dermatitis". Annals of Allergy, Asthma & Immunology. 80 (3): 263–8. doi:10.1016/S1081-1206(10)62968-7. PMID 9532976.
32. Hanifin JM, Schneider LC, Leung DY, Ellis CN, Jaffe HS, Izu AE, et al. (February 1993). "Recombinant interferon gamma therapy for atopic dermatitis". Journal of the American Academy of Dermatology. 28 (2 Pt 1): 189–97. doi:10.1016/0190-9622(93)70026-p. PMID 8432915.
33. Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, et al. (April 2015). "IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer". British Journal of Cancer. 112 (9): 1501–9. doi:10.1038/bjc.2015.101. PMC 4453666. PMID 25867264.
34. Razaghi A, Villacrés C, Jung V, Mashkour N, Butler M, Owens L, Heimann K (October 2017). "Improved therapeutic efficacy of mammalian expressed-recombinant interferon gamma against ovarian cancer cells". Experimental Cell Research. 359 (1): 20–29. doi:10.1016/j.yexcr.2017.08.014. PMID 28803068.
35. Thiel DJ, le Du MH, Walter RL, D'Arcy A, Chène C, Fountoulakis M, et al. (September 2000). "Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex". Structure. 8 (9): 927–36. doi:10.1016/S0969-2126(00)00184-2. PMID 10986460.
36. Kotenko SV, Izotova LS, Pollack BP, Mariano TM, Donnelly RJ, Muthukumaran G, et al. (September 1995). "Interaction between the components of the interferon gamma receptor complex". The Journal of Biological Chemistry. 270 (36): 20915–21. doi:10.1074/jbc.270.36.20915. PMID 7673114.
37. Leon Rodriguez DA, Carmona FD, Echeverría LE, González CI, Martin J (March 2016). "IL18 Gene Variants Influence the Susceptibility to Chagas Disease". PLoS Neglected Tropical Diseases. 10 (3): e0004583. doi:10.1371/journal.pntd.0004583. PMC 4814063. PMID 27027876.
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Further reading

• Hall SK (1997). A commotion in the blood: life, death, and the immune system. New York: Henry Holt. ISBN 978-0-8050-5841-3.
• Ikeda H, Old LJ, Schreiber RD (April 2002). "The roles of IFN gamma in protection against tumor development and cancer immunoediting". Cytokine & Growth Factor Reviews. 13 (2): 95–109. doi:10.1016/S1359-6101(01)00038-7. PMID 11900986.
• Chesler DA, Reiss CS (December 2002). "The role of IFN-gamma in immune responses to viral infections of the central nervous system". Cytokine & Growth Factor Reviews. 13 (6): 441–54. doi:10.1016/S1359-6101(02)00044-8. PMID 12401479.
• Dessein A, Kouriba B, Eboumbou C, Dessein H, Argiro L, Marquet S, et al. (October 2004). "Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in human schistosomiasis". Immunological Reviews. 201: 180–90. doi:10.1111/j.0105-2896.2004.00195.x. PMID 15361241.
• Joseph AM, Kumar M, Mitra D (January 2005). "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.
• Copeland KF (December 2005). "Modulation of HIV-1 transcription by cytokines and chemokines". Mini Reviews in Medicinal Chemistry. 5 (12): 1093–101. doi:10.2174/138955705774933383. PMID 16375755.
• Chiba H, Kojima T, Osanai M, Sawada N (January 2006). "The significance of interferon-gamma-triggered internalization of tight-junction proteins in inflammatory bowel disease". Science's STKE. 2006 (316): pe1. doi:10.1126/stke.3162006pe1. PMID 16391178.
• Tellides G, Pober JS (March 2007). "Interferon-gamma axis in graft arteriosclerosis". Circulation Research. 100 (5): 622–32. CiteSeerX 10.1.1.495.2743. doi:10.1161/01.RES.0000258861.72279.29. PMID 17363708.

External links

• Overview of all the structural information available in the PDB for UniProt: P01579 (Interferon gamma) at the PDBe-KB.

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