Interferon gamma (IFNG or IFN-γ) is adimerized solublecytokine that is the only member of thetype II class ofinterferons.[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 humanleukocytes stimulated withphytohemagglutinin, and by others as a product of antigen-stimulatedlymphocytes.[6] It was also shown to be produced in human lymphocytes.[7] ortuberculin-sensitized mouseperitoneal lymphocytes[8] challenged withMantoux test (PPD); the resultingsupernatants were shown to inhibit growth ofvesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employedinterferon gamma release assay used to test fortuberculosis. In humans, the IFNG protein is encoded by theIFNGgene.[9][10]
Through cell signaling, interferon gamma plays a role in regulating the immune response of its target cell.[11] A key signaling pathway that is activated by type II IFN is theJAK-STAT signaling pathway.[12] IFNG plays an important role in bothinnate andadaptive immunity. Type II IFN is primarily secreted by CD4+T helper 1 (Th1) cells,natural killer (NK) cells, and CD8+cytotoxic T cells. The expression of type II IFN is upregulated and downregulated by cytokines.[13] By activating signaling pathways in cells such asmacrophages,B cells, andCD8+ cytotoxic T cells, it is able to promote inflammation, antiviral or antibacterial activity, and cellproliferation anddifferentiation.[14] Type II IFN is serologically different frominterferon type 1, binds to different receptors, and is encoded by a separate chromosomal locus.[15] Type II IFN has played a role in the development ofcancer immunotherapy treatments due to its ability to prevent tumor growth.[13]
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 induceIgGisotype switching inB cells; upregulatemajor histocompatibility complex (MHC) class II expression onAPCs; induce CD8+ cytotoxic T cell differentiation, activation, and proliferation; and activatemacrophages. In macrophages, type II IFN stimulatesIL-12 expression. IL-12 in turn promotes the secretion of IFNG by NK cells and Th1 cells, and it signalsnaive T helper cells (Th0) to differentiate into Th1 cells.[11]
The IFNGmonomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region.[19][20] 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 IFN-γ monomer.[20]
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 IFN-γ dimer.[20]
The structural models shown in figures 1-3 for IFNG[20] are all shortened at their C-termini by 17 amino acids. Full length IFNG 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.[23] 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.[24] In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFNG-receptor complexes form.[22] 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]
The biological significance of heparan sulfates interaction with IFNG is unclear; however, binding of the D1 cluster to HS may protect it fromproteolytic cleavage.[24]
IFNG 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: theIFNGR1 andIFNGR2. IFNGR1 is associated withJAK1 and IFNGR2 is associated withJAK2. Upon IFNG 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.[12] 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 asapoptosis, intracellularIgG trafficking,cytokine signaling and production,hematopoiesis, and cellproliferation anddifferentiation.[14]
One key pathway triggered by IFNG binding IFNGRs is the Janus Kinase and Signal Transducer and Activator of Transcription pathway, more commonly referred to as theJAK-STAT pathway. In the JAK-STAT pathway, activated JAK1 and JAK2 proteins regulate the phosphorylation of tyrosine inSTAT1 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-STAT1homodimers. The STAT1-STAT1 homodimers can then enter the cell nucleus. They then initiate transcription by binding to gamma interferon activation site (GAS) elements,[12] which are located in the promoter region ofInterferon-stimulated genes (ISGs) that express for antiviral effector proteins, as well as positive and negative regulators of type II IFN signaling pathways.[25]
JAK-STAT signaling pathway activated by type II IFN.
The JAK proteins also lead to the activation of phosphatidylinositol 3-kinase (PI3K). PI3K leads to the activation of protein kinase C delta type (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.[12]
IFNG is secreted byT helper cells (specifically, Th1 cells),cytotoxic T cells (TC cells), macrophages, mucosal epithelial cells andNK cells. IFNG is both an important autocrine signal for professionalAPCs in early innate immune response, and an important paracrine signal in adaptive immune response. The expression of IFNG is induced by the cytokines IL-12, IL-15, IL-18, and type I IFN.[26] IFNG is the only Type IIinterferon and it isserologically distinct from Type I interferons; it is acid-labile, while the type I variants are acid-stable.[citation needed]
IFNG has antiviral, immunoregulatory, and anti-tumor properties.[27] It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are:
Induces the production ofIgG2a andIgG3 from activated plasmaB cells
Causes normal cells to increase expression ofclass I MHC molecules as well asclass II MHC on antigen-presenting cells—to be specific, through induction ofantigen processing genes, including subunits of theimmunoproteasome (MECL1, LMP2, LMP7), as well asTAP andERAAP in addition possibly to the direct upregulation of MHC heavy chains and B2-microglobulin itself
Promotes adhesion and binding required forleukocyte migration
Induces the expression of intrinsic defense factors—for example, with respect toretroviruses, relevant genes includeTRIM5alpha,APOBEC, andTetherin, representing directly antiviral effects
IFNG is the primarycytokine that defines Th1 cells: Th1 cells secrete IFNG, which in turn causes more undifferentiated CD4+ cells (Th0 cells) to differentiate into Th1 cells,[31] representing apositive feedback loop—while suppressing Th2 cell differentiation. (Equivalent defining cytokines for other cells includeIL-4 for Th2 cells andIL-17 forTh17 cells.)
The key association between IFNG and granulomas is that IFNG activates macrophages so that they become more powerful in killing intracellular organisms.[33] Activation of macrophages by IFNG from Th1 helper cells inmycobacterial infections allows the macrophages to overcome the inhibition ofphagolysosome maturation caused by mycobacteria (to stay alive inside macrophages).[34][35] The first steps in IFNG-induced granuloma formation are activation of Th1 helper cells by macrophages releasingIL-1 andIL-12 in the presence of intracellular pathogens, and presentation of antigens from those pathogens. Next the Th1 helper cells aggregate around the macrophages and release IFNG, which activates the macrophages. Further activation of macrophages causes a cycle of further killing of intracellular bacteria, and further presentation of antigens to Th1 helper cells with further release of IFNG. Finally, macrophages surround the Th1 helper cells and become fibroblast-like cells walling off the infection.[citation needed]
Uterine natural killer cells (NKs) secrete high levels ofchemoattractants, such as IFNG in mice. IFNG dilates and thins the walls of maternal spiral arteries to enhance blood flow to theimplantation site. This remodeling aids in the development of the placenta as it invades the uterus in its quest for nutrients. IFNG knockout mice fail to initiate normal pregnancy-induced modification ofdecidual arteries. These models display abnormally low amounts of cells ornecrosis of decidua.[36]
In humans, elevated levels of IFN gamma have been associated with increased risk of miscarriage. Correlation studies have observed high IFNG levels in women with a history of spontaneous miscarriage, when compared to women with no history of spontaneous miscarriage.[37] Additionally, low-IFNG levels are associated with women who successfully carry to term. It is possible that IFNG is cytotoxic totrophoblasts, which leads to miscarriage.[38] However, causal research on the relationship between IFNG and miscarriage has not been performed due toethical constraints.[citation needed]
Recombinant human IFNG, as an expensive biopharmaceutical, has been expressed in different expression systems including prokaryotic, protozoan, fungal (yeasts), plant, insect and mammalian cells. Human IFNG is commonly expressed inEscherichia 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 likePichia pastoris did not show satisfactory results in terms of yields.[39][40]
Interferon gamma 1b is approved by the U.S. Food and Drug Administration to treatchronic granulomatous disease[41] (CGD) andosteopetrosis.[42] The mechanism by which IFNG benefits CGD is via enhancing the efficacy of neutrophils against catalase-positive bacteria by correcting patients' oxidative metabolism.[43]
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.[44] Harkonen was granted a full pardon on January 20, 2021.[45]
Preliminary research on the role of IFNG in treatingFriedreich's ataxia (FA) conducted byChildren's Hospital of Philadelphia has found no beneficial effects in short-term (< 6-months) treatment.[46][47][48] However, researchers in Turkey have discovered significant improvements in patients' gait and stance after 6 months of treatment.[49]
Although not officially approved, Interferon gamma has also been shown to be effective in treating patients with moderate to severeatopic dermatitis.[50][51][52] Specifically, recombinant IFNG therapy has shown promise in patients with lowered IFNG expression, such as those with predisposition to herpes simplex virus, and pediatric patients.[53]
IFNG increases an anti-proliferative state in cancer cells, while upregulating MHC I and MHC II expression, which increases immunorecognition and removal of pathogenic cells.[54] IFNG also reduces metastasis in tumors by upregulatingfibronectin, which negatively impacts tumor architecture.[55] Increased IFNG mRNA levels in tumors at diagnosis has been associated to better responses to immunotherapy.[56]
The goal ofcancer 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 drugdurvalumab to treatnon-small cell lung carcinoma andtransitional 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.[57]
IFNG is not approved yet for the treatment in anycancer immunotherapy. However, improved survival was observed when IFNG was administered to patients withbladder carcinoma andmelanoma cancers. The most promising result was achieved in patients with stage 2 and 3 ofovarian 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."[58] Thein vitro study of IFNG in cancer cells is more extensive and results indicate anti-proliferative activity of IFNG leading to the growth inhibition or cell death, generally induced byapoptosis but sometimes byautophagy.[39] In addition, it has been reported that mammalianglycosylation ofrecombinant human IFNG, expressed inHEK293, improves its therapeutic efficacy compared to the unglycosylated form that is expressed inE. coli.[59]
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 cellapoptosis andnecroptosis (cell death). Furthermore, Type II IFN suppresses the activity ofregulatory T cells, 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 onendothelial 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.[57]
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 theFood and Drug Administration (FDA) to treat cancer, except for malignantosteoporosis. 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 (PDL1), which allows the tumor cells to evade an attack from immune cells. Type II IFN-mediated signaling may also promoteangiogenesis (formation of new blood vessels to the tumor site) and tumor cell proliferation.[57]
Interferon gamma has been shown to be a crucial player in the immune response against some intracellular pathogens, including that ofChagas disease.[62] It has also been identified as having a role in seborrheic dermatitis.[63]
IFNG has a significant anti-viral effect inherpes simplex virus I (HSV) infection. IFNG compromises themicrotubules that HSV relies upon for transport into an infected cell's nucleus, inhibiting the ability of HSV to replicate.[64][65] Studies in mice onacyclovir resistant herpes have shown that IFNG treatment can significantly reduce herpes viral load. The mechanism by which IFNG inhibits herpes reproduction is independent of T-cells, which means that IFNG may be an effective treatment in individuals with low T-cells.[66][67][68]
Chlamydia infection is impacted by IFNG in host cells. In human epithelial cells, IFNG upregulates expression ofindoleamine 2,3-dioxygenase, which in turn depletes tryptophan in hosts and impedes chlamydia's reproduction.[69][70] Additionally, in rodent epithelial cells, IFNG upregulates aGTPase that inhibits chlamydial proliferation.[71] In both the human and rodent systems, chlamydia has evolved mechanisms to circumvent the negative effects of host cell behavior.[72]
There is evidence that interferon-gamma expression is regulated by apseudoknotted element in its 5' UTR.[73]There is also evidence that interferon-gamma is regulated either directly or indirectly by themicroRNAs: miR-29.[74]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.[75]
^Schoenborn JR, Wilson CB (2007). "Regulation of Interferon-γ During Innate and Adaptive Immune Responses".Regulation of interferon-gamma during innate and adaptive immune responses. Advances in Immunology. Vol. 96. pp. 41–101.doi:10.1016/S0065-2776(07)96002-2.ISBN978-0-12-373709-0.PMID17981204.
^Schroder K, Hertzog PJ, Ravasi T, Hume DA (February 2004). "Interferon-gamma: an overview of signals, mechanisms and functions".Journal of Leukocyte Biology.75 (2):163–189.doi:10.1189/jlb.0603252.PMID14525967.S2CID15862242.
^Konjević GM, Vuletić AM, Mirjačić Martinović KM, Larsen AK, Jurišić VB (May 2019). "The role of cytokines in the regulation of NK cells in the tumor environment".Cytokine.117:30–40.doi:10.1016/j.cyto.2019.02.001.PMID30784898.S2CID73482632.
^Mukhopadhyay S, Farver CF, Vaszar LT, Dempsey OJ, Popper HH, Mani H, et al. (January 2012). "Causes of pulmonary granulomas: a retrospective study of 500 cases from seven countries".Journal of Clinical Pathology.65 (1):51–57.doi:10.1136/jclinpath-2011-200336.PMID22011444.S2CID28504428.
^Micallef A, Grech N, Farrugia F, Schembri-Wismayer P, Calleja-Agius J (January 2014). "The role of interferons in early pregnancy".Gynecological Endocrinology.30 (1):1–6.doi:10.3109/09513590.2012.743011.PMID24188446.S2CID207489059.
^Berkowitz RS, Hill JA, Kurtz CB, Anderson DJ (January 1988). "Effects of products of activated leukocytes (lymphokines and monokines) on the growth of malignant trophoblast cells in vitro".American Journal of Obstetrics and Gynecology.158 (1):199–203.doi:10.1016/0002-9378(88)90810-1.PMID2447775.
^abRazaghi 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.PMID27794496.
^Key LL, Ries WL, Rodriguiz RM, Hatcher HC (July 1992). "Recombinant human interferon gamma therapy for osteopetrosis".The Journal of Pediatrics.121 (1):119–124.doi:10.1016/s0022-3476(05)82557-0.PMID1320672.
^Errante PR, Frazão JB, Condino-Neto A (November 2008). "The use of interferon-gamma therapy in chronic granulomatous disease".Recent Patents on Anti-Infective Drug Discovery.3 (3):225–230.doi:10.2174/157489108786242378.PMID18991804.
^Akhavan A, Rudikoff D (June 2008). "Atopic dermatitis: systemic immunosuppressive therapy".Seminars in Cutaneous Medicine and Surgery.27 (2):151–155.doi:10.1016/j.sder.2008.04.004.PMID18620137.
^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):263–268.doi:10.1016/S1081-1206(10)62968-7.PMID9532976.
^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):189–197.doi:10.1016/0190-9622(93)70026-p.PMID8432915.
^Razaghi A, Villacrés C, Jung V, Mashkour N, Butler M, Owens L, et al. (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.PMID28803068.S2CID12800448.
^Khanna KM, Lepisto AJ, Decman V, Hendricks RL (August 2004). "Immune control of herpes simplex virus during latency".Current Opinion in Immunology.16 (4):463–469.doi:10.1016/j.coi.2004.05.003.PMID15245740.
^Rottenberg ME, Gigliotti-Rothfuchs A, Wigzell H (August 2002). "The role of IFN-gamma in the outcome of chlamydial infection".Current Opinion in Immunology.14 (4):444–451.doi:10.1016/s0952-7915(02)00361-8.PMID12088678.
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.PMID11900986.
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):441–454.doi:10.1016/S1359-6101(02)00044-8.PMID12401479.
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.201:180–190.doi:10.1111/j.0105-2896.2004.00195.x.PMID15361241.S2CID25378236.
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.PMID15638726.
Copeland KF (December 2005). "Modulation of HIV-1 transcription by cytokines and chemokines".Mini Reviews in Medicinal Chemistry.5 (12):1093–1101.doi:10.2174/138955705774933383.PMID16375755.
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.PMID16391178.S2CID85320208.
N
Y (what is this?) (verify)
