Просмотр кода страницы Английская Википедия:Interferon gamma

{{Английская Википедия/Панель перехода}}
{{Short description|InterPro Family}}
{{cs1 config|name-list-style=vanc|display-authors = 6 }}
{{#invoke:Infobox_gene|getTemplateData|QID=Q18027639}}
{{Infobox protein family
| Symbol = IFN gamma
| Name = Interferon gamma
| image = PDB 1eku EBI.jpg
| width =
| caption = Crystal structure of a biologically active single chain mutant of human interferon gamma
| Pfam = PF00714
| Pfam_clan = CL0053
| InterPro = IPR002069
| SMART =
| PROSITE =
| MEROPS =
| SCOP = 1rfb
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}
{{Infobox drug
| Verifiedfields = changed
| verifiedrevid = 458270952
| IUPAC_name = Human interferon gamma-1b
<!-- Clinical data -->
| tradename =  Actimmune
| Drugs.com = {{drugs.com|monograph|interferon-gamma}}
| MedlinePlus = a601152
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
| legal_UK = <!-- GSL / P / POM / CD -->
| legal_US = <!-- OTC / Rx-only -->
<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number = 98059-61-1
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 21K6M2I7AG
| ATC_prefix = L03
| ATC_suffix = AB03
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB00033
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201564
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = none
<!-- Chemical data -->
| C=761 | H=1206 | N=214 | O=225 | S=6
}}
'''Interferon gamma''' ('''IFN-γ''') is a [[protein dimer|dimer]]ized soluble [[cytokine]] that is the only member of the '''type II''' class of [[interferon]]s.<ref name="pmid6180322">{{cite journal | vauthors = Gray PW, Goeddel DV | title = Structure of the human immune interferon gene | journal = Nature | volume = 298 | issue = 5877 | pages = 859–863 | date = August 1982 | pmid = 6180322 | doi = 10.1038/298859a0 | s2cid = 4275528 | bibcode = 1982Natur.298..859G }}</ref> 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 [[leukocyte]]s stimulated with [[phytohemagglutinin]], and by others as a product of antigen-stimulated [[lymphocytes]].<ref name="pmid17838106">{{cite journal | vauthors = Wheelock EF | title = Interferon-Like Virus-Inhibitor Induced in Human Leukocytes by Phytohemagglutinin | journal = Science | volume = 149 | issue = 3681 | pages = 310–311 | date = July 1965 | pmid = 17838106 | doi = 10.1126/science.149.3681.310 | s2cid = 1366348 | bibcode = 1965Sci...149..310W }}</ref> It was also shown to be produced in human lymphocytes.<ref>{{cite journal | vauthors = Green JA, Cooperband SR, Kibrick S | title = Immune specific induction of interferon production in cultures of human blood lymphocytes | journal = Science | volume = 164 | issue = 3886 | pages = 1415–1417 | date = June 1969 | pmid = 5783715 | doi = 10.1126/science.164.3886.1415 | s2cid = 32651832 | bibcode = 1969Sci...164.1415G }}</ref> or [[tuberculin]]-sensitized mouse [[peritoneal]] lymphocytes<ref>{{cite journal | vauthors = Milstone LM, Waksman BH | title = Release of virus inhibitor from tuberculin-sensitized peritoneal cells stimulated by antigen | journal = Journal of Immunology | volume = 105 | issue = 5 | pages = 1068–1071 | date = November 1970 | doi = 10.4049/jimmunol.105.5.1068 | pmid = 4321289 | s2cid = 29861335 | doi-access = free }}</ref> challenged with [[Mantoux test]]&nbsp;(PPD); the resulting [[supernatant]]s 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|IFN-γ release assay]] used to test for [[tuberculosis]].  In humans, the IFN-γ protein is encoded by the ''IFNG'' [[gene]].<ref name="pmid6403645">{{cite journal | vauthors = Naylor SL, Sakaguchi AY, Shows TB, Law ML, Goeddel DV, Gray PW | title = Human immune interferon gene is located on chromosome 12 | journal = The Journal of Experimental Medicine | volume = 157 | issue = 3 | pages = 1020–1027 | date = March 1983 | pmid = 6403645 | pmc = 2186972 | doi = 10.1084/jem.157.3.1020 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: IFNGR2 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3460 }}</ref>

Through cell signaling, IFN-γ plays a role in regulating the immune response of its target cell.<ref name=":0" /> A key signaling pathway that is activated by type II IFN is the [[JAK-STAT signaling pathway]].<ref name=":03" /> IFN-γ plays an important role in both [[Innate immune system|innate]] and [[Adaptive immune system|adaptive]] immunity. Type II IFN is primarily secreted by adaptive immune cells, more specifically CD4<sup>+</sup> [[T helper cell|T helper]] 1 (Th1) cells, [[Natural killer cell|natural killer]] (NK) cells, and CD8<sup>+</sup> [[cytotoxic T cell]]s. The expression of type II IFN is upregulated and downregulated by cytokines.<ref name=":2" /> By activating signaling pathways in cells such as [[macrophage]]s, [[B cell]]s, and [[Cytotoxic T cell|CD8<sup>+</sup> cytotoxic T cells]], it is able to promote inflammation, antiviral or antibacterial activity, and cell [[Cell proliferation|proliferation]] and [[Cellular differentiation|differentiation]].<ref name=":1" /> Type II IFN is serologically different from [[interferon type 1]], binds to different receptors, and is encoded by a separate chromosomal locus.<ref>{{cite journal | vauthors = Lee AJ, Ashkar AA | title = The Dual Nature of Type I and Type II Interferons | journal = Frontiers in Immunology | volume = 9 | pages = 2061 | date = 2018 | pmid = 30254639 | pmc = 6141705 | doi = 10.3389/fimmu.2018.02061 | doi-access = free }}</ref> Type II IFN has played a role in the development of [[cancer immunotherapy]] treatments due to its ability to prevent tumor growth.<ref name=":2" />

== Function ==
IFN-γ, or type II interferon, is a cytokine that is critical for [[innate immunity|innate]] and [[adaptive immunity]] against [[Viral disease|viral]], some [[Pathogenic bacteria|bacterial]] and [[protozoan infection]]s. IFN-γ is an important activator of [[macrophage]]s and inducer of [[major histocompatibility complex class II]] molecule expression. Aberrant IFN-γ expression is associated with a number of [[autoinflammatory disease|autoinflammatory]] and [[autoimmune disease]]s. The importance of IFN-γ in the [[immune system]] stems in part from its ability to inhibit [[viral replication]] directly, and most importantly from its [[immunostimulator]]y and [[immunomodulator]]y effects. IFN-γ is produced predominantly by [[natural killer cell]]s (NK) and [[natural killer T cell]]s (NKT) as part of the innate immune response, and by [[CD4]] Th1 and [[CD8]] cytotoxic T lymphocyte ([[Cytotoxic T cell|CTL]]) effector T cells once [[antigen]]-specific immunity develops<ref name="entrez2">{{cite web | title = Entrez Gene: INFG | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3458 }}</ref><ref name="pmid17981204">{{cite book | vauthors = Schoenborn JR, Wilson CB | title = Regulation of interferon-gamma during innate and adaptive immune responses | series = Advances in Immunology | volume = 96 | pages = 41–101 | year = 2007 | pmid = 17981204 | doi = 10.1016/S0065-2776(07)96002-2 | chapter = Regulation of Interferon-γ During Innate and Adaptive Immune Responses | isbn = 978-0-12-373709-0 }}</ref> as part of the adaptive immune response. IFN-γ is also produced by non-cytotoxic [[innate lymphoid cell]]s (ILC), a family of immune cells first discovered in the early 2010s.<ref>{{cite journal | vauthors = Artis D, Spits H | title = The biology of innate lymphoid cells | journal = Nature | volume = 517 | issue = 7534 | pages = 293–301 | date = January 2015 | pmid = 25592534 | doi = 10.1038/nature14189 | s2cid = 4386692 | bibcode = 2015Natur.517..293A }}</ref>

The primary cells that secrete type II IFN are CD4<sup>+</sup> [[T helper cell|T helper]] 1 (Th1) cells, [[Natural killer cell|natural killer]] (NK) cells, and CD8<sup>+</sup> [[cytotoxic T cell]]s. It can also be secreted by antigen presenting cells ([[Antigen-presenting cell|APCs]]) such as dendritic cells ([[Dendritic cell|DCs]]), macrophages ([[Macrophage|MΦs]]), and [[B cell]]s to a lesser degree. Type II IFN expression is upregulated by the production of [[interleukin]] cytokines, such as [[Interleukin 12|IL-12]], [[Interleukin 15|IL-15]], [[Interleukin 18|IL-18]], as well as [[Interferon type I|type I interferons]] (IFN-α and IFN-β).<ref name=":2">{{cite journal | vauthors = Castro F, Cardoso AP, Gonçalves RM, Serre K, Oliveira MJ | title = Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion | journal = Frontiers in Immunology | volume = 9 | pages = 847 | date = 2018 | pmid = 29780381 | pmc = 5945880 | doi = 10.3389/fimmu.2018.00847 | doi-access = free }}</ref> Meanwhile, [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], transforming growth factor-beta ([[Transforming growth factor beta|TGF-β]]) and [[glucocorticoid]]s are known to downregulate type II IFN expression.<ref name=":1">{{cite journal | vauthors = Bhat MY, Solanki HS, Advani J, Khan AA, Keshava Prasad TS, Gowda H, Thiyagarajan S, Chatterjee A | title = Comprehensive network map of interferon gamma signaling | journal = Journal of Cell Communication and Signaling | volume = 12 | issue = 4 | pages = 745–751 | date = December 2018 | pmid = 30191398 | pmc = 6235777 | doi = 10.1007/s12079-018-0486-y }}</ref>

Type II IFN is a cytokine, meaning it functions by signaling to other cells in the immune system and influencing their immune response. There are many immune cells type II IFN acts on. Some of its main functions are to induce [[Immunoglobulin G|IgG]] [[Immunoglobulin class switching|isotype switching]] in [[B cell]]s; upregulate [[MHC class II|major histocompatibility complex (MHC) class II]] expression on [[Antigen-presenting cell|APCs]]; induce CD8<sup>+</sup> cytotoxic T cell differentiation, activation, and proliferation; and activate [[macrophage]]s. In macrophages, type II IFN stimulates [[Interleukin 12|IL-12]] expression. IL-12 in turn promotes the secretion of IFN-γ by NK cells and Th1 cells, and it signals [[Naive T cell|naive T helper cells]] (Th0) to differentiate into Th1 cells.<ref name=":0">{{cite journal | vauthors = Tau G, Rothman P | title = Biologic functions of the IFN-gamma receptors | journal = Allergy | volume = 54 | issue = 12 | pages = 1233–1251 | date = December 1999 | pmid = 10688427 | pmc = 4154595 | doi = 10.1034/j.1398-9995.1999.00099.x }}</ref>

== Structure ==
The IFN-γ [[monomer]] consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region.<ref name="pmid1902591">{{cite journal | vauthors = Ealick SE, Cook WJ, Vijay-Kumar S, Carson M, Nagabhushan TL, Trotta PP, Bugg CE | title = Three-dimensional structure of recombinant human interferon-gamma | journal = Science | volume = 252 | issue = 5006 | pages = 698–702 | date = May 1991 | pmid = 1902591 | doi = 10.1126/science.1902591 | bibcode = 1991Sci...252..698E }}</ref><ref name="PDB_1FG9">{{PDB|1FG9}}; {{cite journal | vauthors = Thiel DJ, le Du MH, Walter RL, D'Arcy A, Chène C, Fountoulakis M, Garotta G, Winkler FK, Ealick SE | title = Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex | journal = Structure | volume = 8 | issue = 9 | pages = 927–936 | date = September 2000 | pmid = 10986460 | doi = 10.1016/S0969-2126(00)00184-2 | doi-access = free }}</ref> This is shown in the structural models below. The α-helices in the core of the structure are numbered 1 to 6.
[[Image:IFN2.jpeg|350px|none|thumb|<span style="font-size:100%;">'''Figure 1.'''</span> Line and cartoon representation of an IFN-γ monomer.<ref name="PDB_1FG9"/>]]

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.
[[Image:IFN3.jpeg|350px|thumb|none|<span style="font-size:100%;">'''Figure 2.'''</span> Line and cartoon representation of an IFN-γ dimer.<ref name="PDB_1FG9"/>]]

== Receptor binding ==
[[Image:IFN with recep.jpeg|250px|thumb|left|<span style="font-size:100%;">'''Figure 3.'''</span> IFN dimer interacting with two [[IFNGR1]] receptor molecules.<ref name="PDB_1FG9"/>]]
{{see also|Interferon-gamma receptor}}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]]. Activation of the JAK-STAT pathway induces upregulation of [[interferon-stimulated gene]]s (ISGs), including MHC II.<ref>{{cite journal | vauthors = Hu X, Ivashkiv LB | title = Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases | journal = Immunity | volume = 31 | issue = 4 | pages = 539–550 | date = October 2009 | pmid = 19833085 | pmc = 2774226 | doi = 10.1016/j.immuni.2009.09.002 }}</ref> 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.<ref name="pmid9556569">{{cite journal | vauthors = Sadir R, Forest E, Lortat-Jacob H | title = The heparan sulfate binding sequence of interferon-gamma increased the on rate of the interferon-gamma-interferon-gamma receptor complex formation | journal = The Journal of Biological Chemistry | volume = 273 | issue = 18 | pages = 10919–10925 | date = May 1998 | pmid = 9556569 | doi = 10.1074/jbc.273.18.10919 | doi-access = free }}</ref>

The structural models shown in figures 1-3 for IFN-γ<ref name="PDB_1FG9"/> are all shortened at their C-termini by 17 amino acids. Full length IFN-γ 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.<ref name="pmid15270718">{{cite journal | vauthors = Vanhaverbeke C, Simorre JP, Sadir R, Gans P, Lortat-Jacob H | title = NMR characterization of the interaction between the C-terminal domain of interferon-gamma and heparin-derived oligosaccharides | journal = The Biochemical Journal | volume = 384 | issue = Pt 1 | pages = 93–99 | date = November 2004 | pmid = 15270718 | pmc = 1134092 | doi = 10.1042/BJ20040757 }}</ref> 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.<ref name="pmid1901275">{{cite journal | vauthors = Lortat-Jacob H, Grimaud JA | title = Interferon-gamma binds to heparan sulfate by a cluster of amino acids located in the C-terminal part of the molecule | journal = FEBS Letters | volume = 280 | issue = 1 | pages = 152–154 | date = March 1991 | pmid = 1901275 | doi = 10.1016/0014-5793(91)80225-R | s2cid = 45942972 | doi-access = free }}</ref> In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFN-γ-receptor complexes form.<ref name="pmid9556569"/> 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.{{citation needed|date=January 2023}}

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]].<ref name="pmid1901275"/>

== Signaling ==
IFN-γ binds to the type II cell-surface receptor, also known as the IFN-gamma receptor (IFNGR) which is part of the class II cytokine receptor family. The IFNGR is composed of two subunits: the [[Interferon gamma receptor 1|IFNGR1]] and [[Interferon gamma receptor 2|IFNGR2]]. IFNGR1 is associated with [[Janus kinase 1|JAK1]] and IFNGR2 is associated with [[Janus kinase 2|JAK2]]. Upon IFN-γ binding the receptor, IFNGR1 and IFNGR2 undergo conformational changes that result in the autophosphorylation and activation of JAK1 and JAK2. This leads to a signaling cascade and eventual transcription of target genes.<ref name=":03">{{cite journal | vauthors = Platanias LC | title = Mechanisms of type-I- and type-II-interferon-mediated signalling | journal = Nature Reviews. Immunology | volume = 5 | issue = 5 | pages = 375–386 | date = May 2005 | pmid = 15864272 | doi = 10.1038/nri1604 | s2cid = 1472195 | doi-access = free }}</ref> The expression of 236 different genes has been linked to type II IFN-mediated signaling. The proteins expressed by type II IFN-mediated signaling are primarily involved in promoting inflammatory immune responses and regulating other cell-mediated immune responses, such as [[apoptosis]], intracellular [[Immunoglobulin G|IgG]] trafficking, [[cytokine]] signaling and production, [[Haematopoiesis|hematopoiesis]], and cell [[Cell proliferation|proliferation]] and [[Cellular differentiation|differentiation]].<ref name=":1" />

=== JAK-STAT pathway ===
One key pathway triggered by IFN-γ binding IFNGRs is the Janus Kinase and Signal Transducer and Activator of Transcription pathway, more commonly referred to as the [[JAK-STAT signaling pathway|JAK-STAT pathway]]. In the JAK-STAT pathway, activated JAK1 and JAK2 proteins regulate the phosphorylation of tyrosine in [[STAT1]] transcription factors. The tyrosines are phosphorylated at a very specific location, allowing activated STAT1 proteins to interact with each other come together to form STAT1-STAT1 [[Protein dimer|homodimers]]. The STAT1-STAT1 homodimers can then enter the cell nucleus. They then initiate transcription by binding to gamma interferon activation site (GAS) elements,<ref name=":03" /> which are located in the promoter region of [[Interferon-stimulated gene|interferon-γ stimulated genes]] (ISGs) that express for antiviral effector proteins, as well as positive and negative regulators of type II IFN signaling pathways.<ref>{{cite journal | vauthors = Schneider WM, Chevillotte MD, Rice CM | title = Interferon-stimulated genes: a complex web of host defenses | journal = Annual Review of Immunology | volume = 32 | issue = 1 | pages = 513–545 | date = 2014-03-21 | pmid = 24555472 | pmc = 4313732 | doi = 10.1146/annurev-immunol-032713-120231 }}</ref>
[[File:Type II IFN JAK-STAT Pathway.jpg|thumb|JAK-STAT signaling pathway activated by type II IFN.]]
The JAK proteins also lead to the activation of phosphatidylinositol 3-kinase ([[Phosphoinositide 3-kinase|PI3K]]). PI3K leads to the activation of protein kinase C-δ ([[PRKCD|PKC-δ]]) which phosphorylates the amino acid serine in STAT1 transcription factors. The phosphorylation of the serine in STAT1-STAT1 homodimers are essential for the full transcription process to occur.<ref name=":03" />

=== Other signaling pathways ===
Other signaling pathways that are triggered by IFN-γ are the [[PI3K/AKT/mTOR pathway|mTOR signaling pathway]], the [[MAPK/ERK pathway|MAPK signaling pathway]], and the [[PI3K/AKT/mTOR pathway|PI3K/AKT signaling pathway]].<ref name=":1" />

== Biological activity ==
IFN-γ is secreted by [[T helper cell]]s (specifically, T<sub>h</sub>1 cells), [[cytotoxic T cell]]s (T<sub>C</sub> cells), macrophages, mucosal epithelial cells and [[NK cells]]. IFN-γ is both an important autocrine signal for professional [[Antigen-presenting cell|APCs]] in early innate immune response, and an important paracrine signal in adaptive immune response. The expression of IFN-γ is induced by the cytokines IL-12, IL-15, IL-18, and type I IFN.<ref>{{cite journal | vauthors = Castro F, Cardoso AP, Gonçalves RM, Serre K, Oliveira MJ | title = Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion | journal = Frontiers in Immunology | volume = 9 | pages = 847 | date = 2018 | pmid = 29780381 | doi = 10.3389/fimmu.2018.00847 | pmc = 5945880 | doi-access = free }}</ref> IFN-γ is the only Type II [[interferon]] and it is [[Serology|serologically]] distinct from Type I interferons; it is acid-labile, while the type I variants are acid-stable.{{citation needed|date=January 2023}}

IFN-γ has antiviral, immunoregulatory, and anti-tumor properties.<ref name="pmid14525967">{{cite journal | vauthors = Schroder K, Hertzog PJ, Ravasi T, Hume DA | title = Interferon-gamma: an overview of signals, mechanisms and functions | journal = Journal of Leukocyte Biology | volume = 75 | issue = 2 | pages = 163–189 | date = February 2004 | pmid = 14525967 | doi = 10.1189/jlb.0603252 | s2cid = 15862242 | doi-access =  }}</ref> It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are:
* Promotes [[NK cell]] activity<ref>{{cite journal | vauthors = Konjević GM, Vuletić AM, Mirjačić Martinović KM, Larsen AK, Jurišić VB | title = The role of cytokines in the regulation of NK cells in the tumor environment | journal = Cytokine | volume = 117 | pages = 30–40 | date = May 2019 | pmid = 30784898 | doi = 10.1016/j.cyto.2019.02.001 | s2cid = 73482632 }}</ref>
* Increases antigen presentation and [[lysosome]] activity of [[macrophage]]s.
* Activates inducible [[nitric oxide synthase]] (iNOS)
* Induces the production of [[IgG2]]a and [[IgG3]] from activated plasma [[B cell]]s
* 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 [[Transporter associated with antigen processing|TAP]] and [[ARTS-1|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 [[retrovirus]]es, relevant genes include [[TRIM5alpha]], [[APOBEC]], and [[Tetherin]], representing directly antiviral effects
* Primes alveolar [[macrophage]]s against secondary bacterial infections.<ref>{{cite journal | vauthors = Hoyer FF, Naxerova K, Schloss MJ, Hulsmans M, Nair AV, Dutta P, Calcagno DM, Herisson F, Anzai A, Sun Y, Wojtkiewicz G, Rohde D, Frodermann V, Vandoorne K, Courties G, Iwamoto Y, Garris CS, Williams DL, Breton S, Brown D, Whalen M, Libby P, Pittet MJ, King KR, Weissleder R, Swirski FK, Nahrendorf M | title = Tissue-Specific Macrophage Responses to Remote Injury Impact the Outcome of Subsequent Local Immune Challenge | journal = Immunity | volume = 51 | issue = 5 | pages = 899–914.e7 | date = November 2019 | pmid = 31732166 | pmc = 6892583 | doi = 10.1016/j.immuni.2019.10.010 }}</ref><ref>{{cite journal | vauthors = Yao Y, Jeyanathan M, Haddadi S, Barra NG, Vaseghi-Shanjani M, Damjanovic D, Lai R, Afkhami S, Chen Y, Dvorkin-Gheva A, Robbins CS, Schertzer JD, Xing Z | title = Induction of Autonomous Memory Alveolar Macrophages Requires T Cell Help and Is Critical to Trained Immunity | journal = Cell | volume = 175 | issue = 6 | pages = 1634–1650.e17 | date = November 2018 | pmid = 30433869 | doi = 10.1016/j.cell.2018.09.042 | doi-access = free }}</ref>

IFN-γ is the primary [[cytokine]] that defines T<sub>h</sub>1 cells: T<sub>h</sub>1 cells secrete IFN-γ, which in turn causes more undifferentiated CD4<sup>+</sup> cells (Th0 cells) to differentiate into T<sub>h</sub>1 cells, <ref>{{cite journal | vauthors = Luckheeram RV, Zhou R, Verma AD, Xia B | title = CD4⁺T cells: differentiation and functions | journal = Clinical & Developmental Immunology | volume = 2012 | pages = 925135 | date = 2012 | pmid = 22474485 | pmc = 3312336 | doi = 10.1155/2012/925135 | doi-access = free }}</ref> representing a [[positive feedback loop]]—while suppressing T<sub>h</sub>2 cell differentiation. (Equivalent defining cytokines for other cells include [[Interleukin 4|IL-4]] for T<sub>h</sub>2 cells and [[Interleukin 17|IL-17]] for [[T helper 17 cell|Th17 cells]].)

[[NK cell]]s and [[CD8+ cytotoxic T cell]]s 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 [[NF-κB]].{{citation needed|date=January 2023}}

===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 nodule]]s, and aspiration of food and other particulate material into the lung.<ref>{{cite journal | vauthors = Mukhopadhyay S, Farver CF, Vaszar LT, Dempsey OJ, Popper HH, Mani H, Capelozzi VL, Fukuoka J, Kerr KM, Zeren EH, Iyer VK, Tanaka T, Narde I, Nomikos A, Gumurdulu D, Arava S, Zander DS, Tazelaar HD | title = Causes of pulmonary granulomas: a retrospective study of 500 cases from seven countries | journal = Journal of Clinical Pathology | volume = 65 | issue = 1 | pages = 51–57 | date = January 2012 | pmid = 22011444 | doi = 10.1136/jclinpath-2011-200336 | s2cid = 28504428 }}</ref> The infectious pathophysiology of granulomas is discussed primarily here.{{citation needed|date=January 2023}}

The key association between IFN-γ and granulomas is that IFN-γ activates macrophages so that they become more powerful in killing intracellular organisms.<ref>{{cite journal | vauthors = Wu C, Xue Y, Wang P, Lin L, Liu Q, Li N, Xu J, Cao X | title = IFN-γ primes macrophage activation by increasing phosphatase and tensin homolog via downregulation of miR-3473b | journal = Journal of Immunology | volume = 193 | issue = 6 | pages = 3036–3044 | date = September 2014 | pmid = 25092892 | doi = 10.4049/jimmunol.1302379 | s2cid = 90897269 | doi-access = free }}</ref> Activation of macrophages by IFN-γ from T<sub>h</sub>1 helper cells in [[mycobacteria]]l infections allows the macrophages to overcome the inhibition of [[phagolysosome]] maturation caused by mycobacteria (to stay alive inside macrophages).<ref>{{cite journal | vauthors = Herbst S, Schaible UE, Schneider BE | title = Interferon gamma activated macrophages kill mycobacteria by nitric oxide induced apoptosis | journal = PLOS ONE | volume = 6 | issue = 5 | pages = e19105 | date = May 2011 | pmid = 21559306 | pmc = 3085516 | doi = 10.1371/journal.pone.0019105 | bibcode = 2011PLoSO...619105H | doi-access = free }}</ref><ref>{{cite journal | vauthors = Harris J, Master SS, De Haro SA, Delgado M, Roberts EA, Hope JC, Keane J, Deretic V | title = Th1-Th2 polarisation and autophagy in the control of intracellular mycobacteria by macrophages | journal = Veterinary Immunology and Immunopathology | volume = 128 | issue = 1–3 | pages = 37–43 | date = March 2009 | pmid = 19026454 | pmc = 2789833 | doi = 10.1016/j.vetimm.2008.10.293 }}</ref> The first steps in IFN-γ-induced granuloma formation are activation of T<sub>h</sub>1 helper cells by macrophages releasing [[interleukin 1|IL-1]] and [[interleukin 12|IL-12]] in the presence of intracellular pathogens, and presentation of antigens from those pathogens. Next the T<sub>h</sub>1 helper cells aggregate around the macrophages and release IFN-γ, which activates the macrophages. Further activation of macrophages causes a cycle of further killing of intracellular bacteria, and further presentation of antigens to T<sub>h</sub>1 helper cells with further release of IFN-γ. Finally, macrophages surround the T<sub>h</sub>1 helper cells and become fibroblast-like cells walling off the infection.{{citation needed|date=January 2023}}

===Activity during pregnancy===
[[Uterine Natural Killer Cells|Uterine Natural Killer cells]] ([[natural killer cell|NK]]) secrete high levels of [[chemoattractant]]s, such as IFN-γ in mice. IFN-γ 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. IFN-γ knockout mice fail to initiate normal pregnancy-induced modification of [[decidual]] arteries. These models display abnormally low amounts of cells or [[necrosis]] of decidua.<ref name="pmid10899912">{{cite journal | vauthors = Ashkar AA, Di Santo JP, Croy BA | title = Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy | journal = The Journal of Experimental Medicine | volume = 192 | issue = 2 | pages = 259–270 | date = July 2000 | pmid = 10899912 | pmc = 2193246 | doi = 10.1084/jem.192.2.259 }}</ref>

In humans, elevated levels of IFN-γ have been associated with increased risk of miscarriage. Correlation studies have observed high IFN-γ levels in women with a history of spontaneous miscarriage, when compared to women with no history of spontaneous miscarriage.<ref>{{cite journal | vauthors = Micallef A, Grech N, Farrugia F, Schembri-Wismayer P, Calleja-Agius J | title = The role of interferons in early pregnancy | journal = Gynecological Endocrinology | volume = 30 | issue = 1 | pages = 1–6 | date = January 2014 | pmid = 24188446 | doi = 10.3109/09513590.2012.743011 | s2cid = 207489059 }}</ref> Additionally, low-IFN-γ levels are associated with women who successfully carry to term. It is possible that IFN-γ is cytotoxic to [[trophoblast]]s, which leads to miscarriage.<ref>{{cite journal | vauthors = Berkowitz RS, Hill JA, Kurtz CB, Anderson DJ | title = Effects of products of activated leukocytes (lymphokines and monokines) on the growth of malignant trophoblast cells in vitro | journal = American Journal of Obstetrics and Gynecology | volume = 158 | issue = 1 | pages = 199–203 | date = January 1988 | pmid = 2447775 | doi = 10.1016/0002-9378(88)90810-1 }}</ref> However, causal research on the relationship between IFN-γ and miscarriage has not been performed due to [[Medical ethics|ethical constraints]].{{citation needed|date=January 2023}}

== Production ==
Recombinant human IFN-γ, as an expensive biopharmaceutical, has been expressed in different expression systems including prokaryotic, protozoan, fungal (yeasts), plant, insect and mammalian cells. Human IFN-γ 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.<ref name="Razaghi A 2016">{{cite journal | vauthors = Razaghi A, Owens L, Heimann K | title = Review of the recombinant human interferon gamma as an immunotherapeutic: Impacts of production platforms and glycosylation | journal = Journal of Biotechnology | volume = 240 | pages = 48–60 | date = December 2016 | pmid = 27794496 | doi = 10.1016/j.jbiotec.2016.10.022 }}</ref><ref>{{cite journal | vauthors = Razaghi A, Tan E, Lua LH, Owens L, Karthikeyan OP, Heimann K | title = Is Pichia pastoris a realistic platform for industrial production of recombinant human interferon gamma? | journal = Biologicals | volume = 45 | pages = 52–60 | date = January 2017 | pmid = 27810255 | doi = 10.1016/j.biologicals.2016.09.015 | s2cid = 28204059 | url = https://zenodo.org/record/1312349 }}</ref>

== Therapeutic use ==

Interferon-γ 1b is approved by the U.S. Food and Drug Administration to treat [[chronic granulomatous disease]]<ref name="pmid1372855">{{cite journal | vauthors = Todd PA, Goa KL | title = Interferon gamma-1b. A review of its pharmacology and therapeutic potential in chronic granulomatous disease | journal = Drugs | volume = 43 | issue = 1 | pages = 111–122 | date = January 1992 | pmid = 1372855 | doi = 10.2165/00003495-199243010-00008 | s2cid = 46986837 }}</ref> (CGD) and [[osteopetrosis]].<ref name="pmid1320672">{{cite journal | vauthors = Key LL, Ries WL, Rodriguiz RM, Hatcher HC | title = Recombinant human interferon gamma therapy for osteopetrosis | journal = The Journal of Pediatrics | volume = 121 | issue = 1 | pages = 119–124 | date = July 1992 | pmid = 1320672 | doi = 10.1016/s0022-3476(05)82557-0 }}</ref> The mechanism by which IFN-γ benefits CGD is via enhancing the efficacy of neutrophils against catalase-positive bacteria by correcting patients' oxidative metabolism.<ref>{{cite journal | vauthors = Errante PR, Frazão JB, Condino-Neto A | title = The use of interferon-gamma therapy in chronic granulomatous disease | journal = Recent Patents on Anti-Infective Drug Discovery | volume = 3 | issue = 3 | pages = 225–230 | date = November 2008 | pmid = 18991804 | doi = 10.2174/157489108786242378 }}</ref>

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.<ref name=Silverman_2013>{{cite journal | vauthors = Silverman E | title = Drug Marketing. The line between scientific uncertainty and promotion of snake oil | journal = BMJ | volume = 347 | pages = f5687 | date = September 2013 | pmid = 24055923 | doi = 10.1136/bmj.f5687 | s2cid = 27716008 }}</ref> Harkonen was granted a full pardon on January 20, 2021.<ref>{{cite web |title=Statement from the Press Secretary Regarding Executive Grants of Clemency |url=https://trumpwhitehouse.archives.gov/briefings-statements/statement-press-secretary-regarding-executive-grants-clemency-012021/ |via=[[NARA|National Archives]] |work=[[whitehouse.gov]] |date=January 20, 2021}}</ref>

Preliminary research on the role of IFN-γ in treating [[Friedreich's ataxia]] (FA) conducted by [[Children’s Hospital of Philadelphia]] has found no beneficial effects in short-term (< 6-months) treatment.<ref>{{cite journal | vauthors = Wells M, Seyer L, Schadt K, Lynch DR | title = IFN-γ for Friedreich ataxia: present evidence | journal = Neurodegenerative Disease Management | volume = 5 | issue = 6 | pages = 497–504 | date = December 2015 | pmid = 26634868 | doi = 10.2217/nmt.15.52 }}</ref><ref name=FA>{{cite journal | vauthors = Seyer L, Greeley N, Foerster D, Strawser C, Gelbard S, Dong Y, Schadt K, Cotticelli MG, Brocht A, Farmer J, Wilson RB, Lynch DR | title = Open-label pilot study of interferon gamma-1b in Friedreich ataxia | journal = Acta Neurologica Scandinavica | volume = 132 | issue = 1 | pages = 7–15 | date = July 2015 | pmid = 25335475 | doi = 10.1111/ane.12337 | s2cid = 207014054 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Lynch DR, Hauser L, McCormick A, Wells M, Dong YN, McCormack S, Schadt K, Perlman S, Subramony SH, Mathews KD, Brocht A, Ball J, Perdok R, Grahn A, Vescio T, Sherman JW, Farmer JM | title = Randomized, double-blind, placebo-controlled study of interferon-''γ'' 1b in Friedreich Ataxia | journal = Annals of Clinical and Translational Neurology | volume = 6 | issue = 3 | pages = 546–553 | date = March 2019 | pmid = 30911578 | pmc = 6414489 | doi = 10.1002/acn3.731 }}</ref> However, researchers in Turkey have discovered significant improvements in patients' gait and stance after 6 months of treatment.<ref>{{cite journal | vauthors = Yetkİn MF, GÜltekİn M | title = Efficacy and Tolerability of Interferon Gamma in Treatment of Friedreich's Ataxia: Retrospective Study | journal = Noro Psikiyatri Arsivi | volume = 57 | issue = 4 | pages = 270–273 | date = December 2020 | pmid = 33354116 | pmc = 7735154 | doi = 10.29399/npa.25047 }}</ref>

Although not officially approved, Interferon-γ has also been shown to be effective in treating patients with moderate to severe [[atopic dermatitis]].<ref>{{cite journal | vauthors = Akhavan A, Rudikoff D | title = Atopic dermatitis: systemic immunosuppressive therapy | journal = Seminars in Cutaneous Medicine and Surgery | volume = 27 | issue = 2 | pages = 151–155 | date = June 2008 | pmid = 18620137 | doi = 10.1016/j.sder.2008.04.004 }}</ref><ref>{{cite journal | vauthors = Schneider LC, Baz Z, Zarcone C, Zurakowski D | title = Long-term therapy with recombinant interferon-gamma (rIFN-gamma) for atopic dermatitis | journal = Annals of Allergy, Asthma & Immunology | volume = 80 | issue = 3 | pages = 263–268 | date = March 1998 | pmid = 9532976 | doi = 10.1016/S1081-1206(10)62968-7 }}</ref><ref>{{cite journal | vauthors = Hanifin JM, Schneider LC, Leung DY, Ellis CN, Jaffe HS, Izu AE, Bucalo LR, Hirabayashi SE, Tofte SJ, Cantu-Gonzales G | title = Recombinant interferon gamma therapy for atopic dermatitis | journal = Journal of the American Academy of Dermatology | volume = 28 | issue = 2 Pt 1 | pages = 189–197 | date = February 1993 | pmid = 8432915 | doi = 10.1016/0190-9622(93)70026-p }}</ref> Specifically, recombinant IFN-γ therapy has shown promise in patients with lowered IFN-γ expression, such as those with predisposition to herpes simplex virus, and pediatric patients.<ref>{{cite journal | vauthors = Brar K, Leung DY | title = Recent considerations in the use of recombinant interferon gamma for biological therapy of atopic dermatitis | journal = Expert Opinion on Biological Therapy | volume = 16 | issue = 4 | pages = 507–514 | date = 2016 | pmid = 26694988 | pmc = 4985031 | doi = 10.1517/14712598.2016.1135898 }}</ref>

==Potential use in immunotherapy==
IFN-γ increases an anti-proliferative state in cancer cells, while upregulating MHC I and MHC II expression, which increases immunorecognition and removal of pathogenic cells.<ref>{{cite journal | vauthors = Kak G, Raza M, Tiwari BK | title = Interferon-gamma (IFN-γ): Exploring its implications in infectious diseases | journal = Biomolecular Concepts | volume = 9 | issue = 1 | pages = 64–79 | date = May 2018 | pmid = 29856726 | doi = 10.1515/bmc-2018-0007 | s2cid = 46922378 | doi-access = free }}</ref> IFN-γ also reduces metastasis in tumors by upregulating [[fibronectin]], which negatively impacts tumor architecture.<ref>{{cite journal | vauthors = Jorgovanovic D, Song M, Wang L, Zhang Y | title = Roles of IFN-γ in tumor progression and regression: a review | journal = Biomarker Research | volume = 8 | issue = 1 | pages = 49 | date = 2020-09-29 | pmid = 33005420 | pmc = 7526126 | doi = 10.1186/s40364-020-00228-x | doi-access = free }}</ref> Increased IFN-γ mRNA levels in tumors at diagnosis has been associated to better responses to immunotherapy.<ref>{{cite journal | vauthors = Casarrubios M, Provencio M, Nadal E, Insa A, del Rosario García-Campelo M, Lázaro-Quintela M, Dómine M, Majem M, Rodriguez-Abreu D, Martinez-Marti A, De Castro Carpeño J, Cobo M, López Vivanco G, Del Barco E, Bernabé R, Viñolas N, Barneto Aranda I, Massuti B, Sierra-Rodero B, Martinez-Toledo C, Fernández-Miranda I, Serna-Blanco R, Romero A, Calvo V, Cruz-Bermúdez A   |title=Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy |journal=Journal for ImmunoTherapy of Cancer |date=September 2022 |volume=10 |issue=9 |pages=e005320 |doi=10.1136/jitc-2022-005320|pmid=36171009 |pmc=9528578 |hdl=2445/190198 |hdl-access=free }}</ref>

=== Cancer immunotherapy ===
The goal of [[cancer immunotherapy]] is to trigger an immune response by the patient's immune cells to attack and kill malignant (cancer-causing) tumor cells. Type II IFN deficiency has been linked to several types of cancer, including B-cell lymphoma and lung cancer. Furthermore, it has been found that in patients receiving the drug [[durvalumab]] to treat [[Non-small-cell lung carcinoma|non-small cell lung carcinoma]] and [[transitional cell carcinoma]] had higher response rates to the drug, and the drug stunted the progression of both types of cancer for a longer duration of time. Thus, promoting the upregulation of type II IFN has been proven to be a crucial part in creating effective cancer immunotherapy treatments.<ref name=":22">{{cite journal | vauthors = Ni L, Lu J | title = Interferon gamma in cancer immunotherapy | journal = Cancer Medicine | volume = 7 | issue = 9 | pages = 4509–4516 | date = September 2018 | pmid = 30039553 | pmc = 6143921 | doi = 10.1002/cam4.1700 }}</ref>

IFN-γ is not approved yet for the treatment in any [[cancer immunotherapy]]. However, improved survival was observed when IFN-γ was administered 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."<ref>{{cite journal | vauthors = Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, Yoshioka Y, Baba T, Konishi I, Mandai M | title = IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer | journal = British Journal of Cancer | volume = 112 | issue = 9 | pages = 1501–1509 | date = April 2015 | pmid = 25867264 | pmc = 4453666 | doi = 10.1038/bjc.2015.101 }}</ref> The ''[[in vitro]]'' study of IFN-γ in cancer cells is more extensive and results indicate anti-proliferative activity of IFN-γ leading to the growth inhibition or cell death, generally induced by [[apoptosis]] but sometimes by [[autophagy]].<ref name="Razaghi A 2016" /> In addition, it has been reported that mammalian [[glycosylation]] of [[recombinant protein|recombinant]] human IFN-γ, expressed in [[HEK 293 cells|HEK293]], improves its therapeutic efficacy compared to the unglycosylated form that is expressed in ''[[Escherichia coli|E. coli]]''.<ref>{{cite journal | vauthors = Razaghi A, Villacrés C, Jung V, Mashkour N, Butler M, Owens L, Heimann K | title = Improved therapeutic efficacy of mammalian expressed-recombinant interferon gamma against ovarian cancer cells | journal = Experimental Cell Research | volume = 359 | issue = 1 | pages = 20–29 | date = October 2017 | pmid = 28803068 | doi = 10.1016/j.yexcr.2017.08.014 | s2cid = 12800448 }}</ref>

=== Involvement in antitumor immunity ===
Type II IFN enhances Th1 cell, cytotoxic T cell, and APC activities, which results in an enhanced immune response against the malignant tumor cells, leading to tumor cell [[apoptosis]] and [[necroptosis]] (cell death). Furthermore, Type II IFN suppresses the activity of [[regulatory T cell]]s, which are responsible for silencing immune responses against pathogens, preventing the deactivation of the immune cells involved in the killing of the tumor cells. Type II IFN prevents tumor cell division by directly acting on the tumor cells, which results in increased expression of proteins that inhibit the tumor cells from continuing through the cell cycle (i.e., cell cycle arrest). Type II IFN can also prevent tumor growth by indirectly acting on [[Endothelium|endothelial cells]] lining the blood vessels close to the site of the tumor, cutting off blood flow to the tumor cells and thus the supply of necessary resources for tumor cell survival and proliferation.<ref name=":22" />

=== Barriers ===
The importance of type II IFN in cancer immunotherapy has been acknowledged; current research is studying the effects of type II IFN on cancer, both as a solo form of treatment and as a form of treatment to be administered alongside other anticancer drugs. But type II IFN has not been approved by the [[Food and Drug Administration|Food and Drug Administration (FDA)]] to treat cancer, except for malignant [[osteoporosis]]. This is most likely due to the fact that while type II IFN is involved in antitumor immunity, some of its functions may enhance the progression of a cancer. When type II IFN acts on tumor cells, it may induce the expression of a transmembrane protein known as programmed death-ligand 1 ([[PD-L1|PDL1]]), which allows the tumor cells to evade an attack from immune cells. Type II IFN-mediated signaling may also promote [[angiogenesis]] (formation of new blood vessels to the tumor site) and tumor cell proliferation.<ref name=":22" />

== Interactions ==
Interferon-γ has been shown to [[Protein-protein interaction|interact]] with [[Interferon gamma receptor 1]] and [[Interferon gamma receptor 2]].<ref name="pmid10986460">{{cite journal | vauthors = Thiel DJ, le Du MH, Walter RL, D'Arcy A, Chène C, Fountoulakis M, Garotta G, Winkler FK, Ealick SE | title = Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex | journal = Structure | volume = 8 | issue = 9 | pages = 927–936 | date = September 2000 | pmid = 10986460 | doi = 10.1016/S0969-2126(00)00184-2 | doi-access = free }}</ref><ref name="pmid7673114">{{cite journal | vauthors = Kotenko SV, Izotova LS, Pollack BP, Mariano TM, Donnelly RJ, Muthukumaran G, Cook JR, Garotta G, Silvennoinen O, Ihle JN | title = Interaction between the components of the interferon gamma receptor complex | journal = The Journal of Biological Chemistry | volume = 270 | issue = 36 | pages = 20915–20921 | date = September 1995 | pmid = 7673114 | doi = 10.1074/jbc.270.36.20915 | doi-access = free }}</ref>

===Diseases===
Interferon-γ has been shown to be a crucial player in the immune response against some intracellular pathogens, including that of [[Chagas disease]].<ref>{{cite journal | vauthors = Leon Rodriguez DA, Carmona FD, Echeverría LE, González CI, Martin J | title = IL18 Gene Variants Influence the Susceptibility to Chagas Disease | journal = PLOS Neglected Tropical Diseases | volume = 10 | issue = 3 | pages = e0004583 | date = March 2016 | pmid = 27027876 | pmc = 4814063 | doi = 10.1371/journal.pntd.0004583 | doi-access = free }}</ref> It has also been identified as having a role in seborrheic dermatitis.<ref>{{cite journal | vauthors = Trznadel-Grodzka E, Błaszkowski M, Rotsztejn H | title = Investigations of seborrheic dermatitis. Part I. The role of selected cytokines in the pathogenesis of seborrheic dermatitis | journal = Postepy Higieny I Medycyny Doswiadczalnej | volume = 66 | pages = 843–847 | date = November 2012 | pmid = 23175340 | doi = 10.5604/17322693.1019642 | doi-access = free }}</ref>

IFN-γ has a significant anti-viral effect in [[herpes simplex virus]] I (HSV) infection.  IFN-γ compromises the [[microtubule]]s that HSV relies upon for transport into an infected cell's nucleus, inhibiting the ability of HSV to replicate.<ref>{{cite journal | vauthors = Bigley NJ | title = Complexity of Interferon-γ Interactions with HSV-1 | journal = Frontiers in Immunology | volume = 5 | pages = 15 | date = 2014-02-06 | pmid = 24567732 | pmc = 3915238 | doi = 10.3389/fimmu.2014.00015 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sodeik B, Ebersold MW, Helenius A | title = Microtubule-mediated transport of incoming herpes simplex virus 1 capsids to the nucleus | journal = The Journal of Cell Biology | volume = 136 | issue = 5 | pages = 1007–1021 | date = March 1997 | pmid = 9060466 | pmc = 2132479 | doi = 10.1083/jcb.136.5.1007 }}</ref> Studies in mice on [[acyclovir]] resistant herpes have shown that IFN-γ treatment can significantly reduce herpes viral load. The mechanism by which IFN-γ inhibits herpes reproduction is independent of T-cells, which means that IFN-γ may be an effective treatment in individuals with low T-cells.<ref>{{cite journal | vauthors = Huang WY, Su YH, Yao HW, Ling P, Tung YY, Chen SH, Wang X, Chen SH | title = Beta interferon plus gamma interferon efficiently reduces acyclovir-resistant herpes simplex virus infection in mice in a T-cell-independent manner | journal = The Journal of General Virology | volume = 91 | issue = Pt 3 | pages = 591–598 | date = March 2010 | pmid = 19906941 | doi = 10.1099/vir.0.016964-0 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sainz B, Halford WP | title = Alpha/Beta interferon and gamma interferon synergize to inhibit the replication of herpes simplex virus type 1 | journal = Journal of Virology | volume = 76 | issue = 22 | pages = 11541–11550 | date = November 2002 | pmid = 12388715 | pmc = 136787 | doi = 10.1128/JVI.76.22.11541-11550.2002 }}</ref><ref>{{cite journal | vauthors = Khanna KM, Lepisto AJ, Decman V, Hendricks RL | title = Immune control of herpes simplex virus during latency | journal = Current Opinion in Immunology | volume = 16 | issue = 4 | pages = 463–469 | date = August 2004 | pmid = 15245740 | doi = 10.1016/j.coi.2004.05.003 }}</ref>

[[Chlamydia]] infection is impacted by IFN-γ in host cells. In human epithelial cells, IFN-γ upregulates expression of [[indoleamine 2,3-dioxygenase]], which in turn depletes tryptophan in hosts and impedes chlamydia's reproduction.<ref>{{cite journal | vauthors = Rottenberg ME, Gigliotti-Rothfuchs A, Wigzell H | title = The role of IFN-gamma in the outcome of chlamydial infection | journal = Current Opinion in Immunology | volume = 14 | issue = 4 | pages = 444–451 | date = August 2002 | pmid = 12088678 | doi = 10.1016/s0952-7915(02)00361-8 }}</ref><ref>{{cite journal | vauthors = Taylor MW, Feng GS | title = Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism | journal = FASEB Journal | volume = 5 | issue = 11 | pages = 2516–2522 | date = August 1991 | pmid = 1907934 | doi = 10.1096/fasebj.5.11.1907934 | doi-access = free | s2cid = 25298471 }}</ref> Additionally, in rodent epithelial cells, IFN-γ upregulates a [[GTPase]] that inhibits chlamydial proliferation.<ref>{{cite journal | vauthors = Bernstein-Hanley I, Coers J, Balsara ZR, Taylor GA, Starnbach MN, Dietrich WF | title = The p47 GTPases Igtp and Irgb10 map to the Chlamydia trachomatis susceptibility locus Ctrq-3 and mediate cellular resistance in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 38 | pages = 14092–14097 | date = September 2006 | pmid = 16959883 | pmc = 1599917 | doi = 10.1073/pnas.0603338103 | bibcode = 2006PNAS..10314092B | doi-access = free }}</ref> In both the human and rodent systems, chlamydia has evolved mechanisms to circumvent the negative effects of host cell behavior.<ref>{{cite journal | vauthors = Nelson DE, Virok DP, Wood H, Roshick C, Johnson RM, Whitmire WM, Crane DD, Steele-Mortimer O, Kari L, McClarty G, Caldwell HD | title = Chlamydial IFN-gamma immune evasion is linked to host infection tropism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 30 | pages = 10658–10663 | date = July 2005 | pmid = 16020528 | pmc = 1180788 | doi = 10.1073/pnas.0504198102 | bibcode = 2005PNAS..10210658N | doi-access = free }}</ref>

==Regulation==
There is evidence that interferon-gamma expression is regulated by a [[Interferon gamma 5' UTR regulatory element|pseudoknotted element in its 5' UTR]].<ref>{{cite journal | vauthors = Ben-Asouli Y, Banai Y, Pel-Or Y, Shir A, Kaempfer R | title = Human interferon-gamma mRNA autoregulates its translation through a pseudoknot that activates the interferon-inducible protein kinase PKR | journal = Cell | volume = 108 | issue = 2 | pages = 221–232 | date = January 2002 | pmid = 11832212 | doi = 10.1016/S0092-8674(02)00616-5 | s2cid = 14722737 | doi-access = free }}</ref>
There is also evidence that interferon-gamma is regulated either directly or indirectly by the [[microRNAs]]: miR-29.<ref name="pmid18061676">{{cite journal | vauthors = Asirvatham AJ, Gregorie CJ, Hu Z, Magner WJ, Tomasi TB | title = MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components | journal = Molecular Immunology | volume = 45 | issue = 7 | pages = 1995–2006 | date = April 2008 | pmid = 18061676 | pmc = 2678893 | doi = 10.1016/j.molimm.2007.10.035 }}</ref>
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.<ref name="pmid23746840">{{cite journal | vauthors = Chang CH, Curtis JD, Maggi LB, Faubert B, Villarino AV, O'Sullivan D, Huang SC, van der Windt GJ, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones RG, Pearce EL | title = Posttranscriptional control of T cell effector function by aerobic glycolysis | journal = Cell | volume = 153 | issue = 6 | pages = 1239–1251 | date = June 2013 | pmid = 23746840 | pmc = 3804311 | doi = 10.1016/j.cell.2013.05.016 }}</ref>

== References ==
{{Reflist|32em}}

== Further reading ==
{{refbegin|32em}}
* {{cite book | vauthors = Hall SK | title = A commotion in the blood: life, death, and the immune system | publisher = Henry Holt | location = New York | year = 1997 | isbn = 978-0-8050-5841-3 | url =https://archive.org/details/commotioninblood00hall| url-access = registration }}
* {{cite journal | vauthors = Ikeda H, Old LJ, Schreiber RD | title = The roles of IFN gamma in protection against tumor development and cancer immunoediting | journal = Cytokine & Growth Factor Reviews | volume = 13 | issue = 2 | pages = 95–109 | date = April 2002 | pmid = 11900986 | doi = 10.1016/S1359-6101(01)00038-7 }}
* {{cite journal | vauthors = Chesler DA, Reiss CS | title = The role of IFN-gamma in immune responses to viral infections of the central nervous system | journal = Cytokine & Growth Factor Reviews | volume = 13 | issue = 6 | pages = 441–454 | date = December 2002 | pmid = 12401479 | doi = 10.1016/S1359-6101(02)00044-8 }}
* {{cite journal | vauthors = Dessein A, Kouriba B, Eboumbou C, Dessein H, Argiro L, Marquet S, Elwali NE, Rodrigues V, Li Y, Doumbo O, Chevillard C | title = Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in human schistosomiasis | journal = Immunological Reviews | volume = 201 | pages = 180–190 | date = October 2004 | pmid = 15361241 | doi = 10.1111/j.0105-2896.2004.00195.x | s2cid = 25378236 }}
* {{cite journal | vauthors = Joseph AM, Kumar M, Mitra D | title = Nef: "necessary and enforcing factor" in HIV infection | journal = Current HIV Research | volume = 3 | issue = 1 | pages = 87–94 | date = January 2005 | pmid = 15638726 | doi = 10.2174/1570162052773013 }}
* {{cite journal | vauthors = Copeland KF | title = Modulation of HIV-1 transcription by cytokines and chemokines | journal = Mini Reviews in Medicinal Chemistry | volume = 5 | issue = 12 | pages = 1093–1101 | date = December 2005 | pmid = 16375755 | doi = 10.2174/138955705774933383 }}
* {{cite journal | vauthors = Chiba H, Kojima T, Osanai M, Sawada N | title = The significance of interferon-gamma-triggered internalization of tight-junction proteins in inflammatory bowel disease | journal = Science's STKE | volume = 2006 | issue = 316 | pages = pe1 | date = January 2006 | pmid = 16391178 | doi = 10.1126/stke.3162006pe1 | s2cid = 85320208 }}
* {{cite journal | vauthors = Tellides G, Pober JS | title = Interferon-gamma axis in graft arteriosclerosis | journal = Circulation Research | volume = 100 | issue = 5 | pages = 622–632 | date = March 2007 | pmid = 17363708 | doi = 10.1161/01.RES.0000258861.72279.29 | s2cid = 254247 | citeseerx = 10.1.1.495.2743 }}
{{refend}}

== External links ==
* {{PDBe-KB2|P01579|Interferon gamma}}
* {{MeshName|Interferon+Type+II}}
* {{cite web |url=https://druginfo.nlm.nih.gov/drugportal/name/interferon%20type%20ii |publisher=U.S. National Library of Medicine |work=Drug Information Portal |title=Interferon type II}}

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