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55-502: The four JAK family members are: Transgenic mice that do not express JAK1 have defective responses to some cytokines, such as interferon-gamma . JAK1 and JAK2 are involved in type II interferon (interferon-gamma) signalling, whereas JAK1 and TYK2 are involved in type I interferon signalling. Mice that do not express TYK2 have defective natural killer cell function. Since members of the type I and type II cytokine receptor families possess no catalytic kinase activity, they rely on

110-428: A GTPase that inhibits chlamydial proliferation. In both the human and rodent systems, chlamydia has evolved mechanisms to circumvent the negative effects of host cell behavior. There is evidence that interferon-gamma expression is regulated by a pseudoknotted element in its 5' UTR . There is also evidence that interferon-gamma is regulated either directly or indirectly by the microRNAs : miR-29. Furthermore, there

165-502: A positive feedback loop —while suppressing T h 2 cell differentiation. (Equivalent defining cytokines for other cells include IL-4 for T h 2 cells and IL-17 for Th17 cells .) NK cells and CD8+ cytotoxic T cells also produce IFNG. IFNG suppresses osteoclast formation by rapidly degrading the RANK adaptor protein TRAF6 in the RANK - RANKL signaling pathway, which otherwise stimulates

220-616: A history of spontaneous miscarriage, when compared to women with no history of spontaneous miscarriage. Additionally, low-IFNG levels are associated with women who successfully carry to term. It is possible that IFNG is cytotoxic to trophoblasts , which leads to miscarriage. However, causal research on the relationship between IFNG and miscarriage has not been performed due to ethical constraints . 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

275-572: A larger structure (called a supramolecular assembly ). Using molecular biology techniques, fusion proteins of specific enzymes and SH2 domains have been created, which can bind to each other to form protein assemblies. Since SH2 domains require phosphorylation in order for binding to occur, the use of kinase and phosphatase enzymes gives researchers control over whether protein assemblies will form or not. High affinity engineered SH2 domains have been developed and utilized for protein assembly applications. The goal of most protein assembly formation

330-648: A phosphotyrosine-containing protein to an SH2 domain may lead to either activation or inactivation of the SH2-containing protein, depending on the types of interactions formed between the SH2 domain and other domains of the enzyme. Mutations that disrupt the structural stability of the SH2 domain, or that affect the binding of the phosphotyrosine peptide of the target, are involved in a range of diseases including X-linked agammaglobulinemia and severe combined immunodeficiency . SH2 domains are not present in yeast and appear at

385-508: 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

440-452: A role in seborrheic dermatitis. IFNG has a significant anti-viral effect in herpes simplex virus I (HSV) infection. IFNG compromises the microtubules that HSV relies upon for transport into an infected cell's nucleus, inhibiting the ability of HSV to replicate. Studies in mice on acyclovir resistant herpes have shown that IFNG treatment can significantly reduce herpes viral load. The mechanism by which IFNG inhibits herpes reproduction

495-522: Is a dimerized soluble cytokine that is the only member of the type II class of interferons . The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin , and by others as a product of antigen-stimulated lymphocytes . It was also shown to be produced in human lymphocytes. or tuberculin -sensitized mouse peritoneal lymphocytes challenged with Mantoux test  (PPD);

550-564: Is a cytokine that is critical for innate and adaptive immunity against viral , some bacterial and protozoan infections . IFNG is an important activator of macrophages and inducer of major histocompatibility complex class II molecule expression. Aberrant IFNG expression is associated with a number of autoinflammatory and autoimmune diseases . The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects. IFNG

605-523: 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 IgG isotype switching in B cells ; upregulate major histocompatibility complex (MHC) class II expression on APCs ; induce CD8 cytotoxic T cell differentiation, activation, and proliferation; and activate macrophages . In macrophages, type II IFN stimulates IL-12 expression. IL-12 in turn promotes

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660-424: Is able to promote inflammation, antiviral or antibacterial activity, and cell proliferation and differentiation . Type II IFN is serologically different from interferon type 1 , binds to different receptors, and is encoded by a separate chromosomal locus. Type II IFN has played a role in the development of cancer immunotherapy treatments due to its ability to prevent tumor growth. IFNG, or type II interferon,

715-500: Is activated by type II IFN is the JAK-STAT signaling pathway . IFNG plays an important role in both innate and adaptive 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. By activating signaling pathways in cells such as macrophages , B cells , and CD8 cytotoxic T cells , it

770-401: Is approved by the U.S. Food and Drug Administration to treat chronic granulomatous disease (CGD) and osteopetrosis . The mechanism by which IFNG benefits CGD is via enhancing the efficacy of neutrophils against catalase-positive bacteria by correcting patients' oxidative metabolism. It was not approved to treat idiopathic pulmonary fibrosis (IPF). In 2002, the manufacturer InterMune issued

825-500: Is called a FERM domain (short for band 4.1 , ezrin , radixin and moesin ); this domain is also found in the focal adhesion kinase (FAK) family and is involved in association of JAKs with cytokine receptors and/or other kinases. Interferon-gamma 1EKU , 1FG9 , 1FYH , 1HIG , 3BES 3458 15978 ENSG00000111537 ENSMUSG00000055170 P01579 P01580 NM_000619 NM_008337 NP_000610 NP_032363 Interferon gamma ( IFNG or IFN-γ)

880-476: 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. Interferon gamma 1b

935-612: 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. This article incorporates text from the United States National Library of Medicine , which is in the public domain . SH2 domain The SH2 ( S rc H omology 2 ) domain is a structurally conserved protein domain contained within

990-404: Is independent of T-cells, which means that IFNG may be an effective treatment in individuals with low T-cells. Chlamydia infection is impacted by IFNG in host cells. In human epithelial cells, IFNG upregulates expression of indoleamine 2,3-dioxygenase , which in turn depletes tryptophan in hosts and impedes chlamydia's reproduction. Additionally, in rodent epithelial cells, IFNG upregulates

1045-939: Is part of the class II cytokine receptor family. The IFNGR is composed of two subunits: the IFNGR1 and IFNGR2 . IFNGR1 is associated with JAK1 and IFNGR2 is associated with JAK2 . 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. 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 IgG trafficking, cytokine signaling and production, hematopoiesis , and cell proliferation and differentiation . One key pathway triggered by IFNG binding IFNGRs

1100-405: Is produced predominantly by natural killer cells (NK) and natural killer T cells (NKT) 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 as part of the adaptive immune response. IFNG is also produced by non-cytotoxic innate lymphoid cells (ILC), a family of immune cells first discovered in

1155-409: Is secreted by T helper cells (specifically, T h 1 cells), cytotoxic T cells (T C cells), macrophages, mucosal epithelial cells and NK cells . IFNG is both an important autocrine signal for professional APCs 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. IFNG

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1210-634: Is the Janus Kinase and Signal Transducer and Activator of Transcription pathway, more commonly referred to as the 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 homodimers . The STAT1-STAT1 homodimers can then enter

1265-556: 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. IFNG has antiviral, immunoregulatory, and anti-tumor properties. It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are: IFNG is the primary cytokine that defines T h 1 cells: T h 1 cells secrete IFNG, which in turn causes more undifferentiated CD4 cells (Th0 cells) to differentiate into T h 1 cells, representing

1320-415: 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 and transitional cell carcinoma had higher response rates to

1375-449: The 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 ( PDL1 ), which allows

1430-521: The Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains bind to phosphorylated tyrosine residues on other proteins, modifying the function or activity of the SH2-containing protein. The SH2 domain may be considered the prototypical modular protein-protein interaction domain, allowing the transmission of signals controlling a variety of cellular functions. SH2 domains are especially common in adaptor proteins that aid in

1485-484: 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 IFNG to HS inhibits its biological activity. The structural models shown in figures 1-3 for IFNG 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

1540-446: The JAK family of tyrosine kinases to phosphorylate and activate downstream proteins involved in their signal transduction pathways. The receptors exist as paired polypeptides, thus exhibiting two intracellular signal-transducing domains. JAKs associate with a proline -rich region in each intracellular domain that is adjacent to the cell membrane and called a box1/box2 region. After

1595-751: The T h 1 helper cells and become fibroblast-like cells walling off the infection. Uterine natural killer cells (NKs) secrete high levels of chemoattractants , such as IFNG in mice. IFNG 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. IFNG knockout mice fail to initiate normal pregnancy-induced modification of decidual arteries. These models display abnormally low amounts of cells or necrosis of decidua. 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

1650-1342: The U.S. Court of Appeals for the Ninth Circuit, and lost. Harkonen was granted a full pardon on January 20, 2021. Preliminary research on the role of IFNG in treating Friedreich's ataxia (FA) conducted by Children's Hospital of Philadelphia has found no beneficial effects in short-term (< 6-months) treatment. However, researchers in Turkey have discovered significant improvements in patients' gait and stance after 6 months of treatment. Although not officially approved, Interferon gamma has also been shown to be effective in treating patients with moderate to severe atopic dermatitis . 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. 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. IFNG also reduces metastasis in tumors by upregulating fibronectin , which negatively impacts tumor architecture. Increased IFNG mRNA levels in tumors at diagnosis has been associated to better responses to immunotherapy. The goal of cancer immunotherapy

1705-612: 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. Other signaling pathways that are triggered by IFNG are the mTOR signaling pathway , the MAPK signaling pathway , and the PI3K/AKT signaling pathway . IFNG

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1760-662: The boundary between protozoa and animalia in organisms such as the social amoeba Dictyostelium discoideum . A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 115 proteins encoded by the human genome, representing a rapid rate of evolutionary expansion among the SH2 domains. A large number of SH2 domain structures have been solved and many SH2 proteins have been knocked out in mice. SH2 domains, and other binding domains , have been used in protein engineering to create protein assemblies. Protein assemblies are formed when several proteins bind to one another to create

1815-425: The cell nucleus. They then initiate transcription by binding to gamma interferon activation site (GAS) elements, which are located in the promoter region of Interferon-stimulated genes (ISGs) that express for antiviral effector proteins, as well as positive and negative regulators of type II IFN signaling pathways. The JAK proteins also lead to the activation of phosphatidylinositol 3-kinase ( PI3K ). PI3K leads to

1870-580: The conformational changes in the JAK protein to facilitate binding of substrate . JH2 is a pseudokinase domain , a domain structurally similar to a tyrosine kinase and essential for a normal kinase activity, yet lacks enzymatic activity. This domain may be involved in regulating the activity of JH1, and was likely a duplication of the JH1 domain which has undergone mutation post-duplication. The JH3-JH4 domains of JAKs share homology with Src-homology -2 ( SH2 ) domains. The amino terminal (NH 2 ) end (JH4-JH7) of Jaks

1925-425: 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 endothelial cells lining the blood vessels close to

1980-450: The deleted sequence of 17 amino acids. Within this sequence of 17 amino acids lie two clusters of basic amino acids termed D1 and D2, respectively. Heparan sulfate interacts with both of these clusters. In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFNG-receptor complexes form. Interactions between the D1 cluster of amino acids and the receptor may be

2035-472: 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. IFNG is not approved yet for the treatment in any cancer immunotherapy . However, improved survival was observed when IFNG was administered to patients with bladder carcinoma and melanoma cancers. The most promising result

2090-633: The early 2010s. The primary cells that secrete type II IFN are CD4 T helper 1 (Th1) cells, natural killer (NK) cells, and CD8 cytotoxic T cells . It can also be secreted by antigen presenting cells ( APCs ) such as dendritic cells ( DCs ), macrophages ( MΦs ), and B cells to a lesser degree. Type II IFN expression is upregulated by the production of interleukin cytokines, such as IL-12 , IL-15 , IL-18 , as well as type I interferons (IFN-α and IFN-β). Meanwhile, IL-4 , IL-10 , transforming growth factor-beta (TGF-β) and glucocorticoids are known to downregulate type II IFN expression. Type II IFN

2145-457: 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 IFNG is unclear; however, binding of the D1 cluster to HS may protect it from proteolytic cleavage . IFNG binds to the type II cell-surface receptor, also known as the IFN gamma receptor (IFNGR) which

2200-665: The lung. The infectious pathophysiology of granulomas is discussed primarily here. The key association between IFNG and granulomas is that IFNG activates macrophages so that they become more powerful in killing intracellular organisms. Activation of macrophages by IFNG from T h 1 helper cells in mycobacterial infections allows the macrophages to overcome the inhibition of phagolysosome maturation caused by mycobacteria (to stay alive inside macrophages). The first steps in IFNG-induced granuloma formation are activation of T h 1 helper cells by macrophages releasing IL-1 and IL-12 in

2255-421: The presence of intracellular pathogens, and presentation of antigens from those pathogens. Next the T h 1 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 T h 1 helper cells with further release of IFNG. Finally, macrophages surround

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2310-647: The production of NF-κB . 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

2365-475: The receptor and form dimers before translocating to the cell nucleus , where they regulate transcription of selected genes . Some examples of the molecules that use the JAK/STAT signaling pathway are colony-stimulating factor , prolactin , growth hormone , and many cytokines . Janus Kinases have also been reported to have a role in the maintenance of X chromosome inactivation . JAK inhibitors are used for

2420-508: The receptor associates with its respective cytokine / ligand , it goes through a conformational change, bringing the two JAKs close enough to phosphorylate each other. The JAK autophosphorylation induces a conformational change within itself, enabling it to transduce the intracellular signal by further phosphorylating and activating transcription factors called STATs (Signal Transducer and Activator of Transcription, or Signal Transduction And Transcription) . The activated STATs dissociate from

2475-540: 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 IFNG protein is encoded by the IFNG gene . Through cell signaling, interferon gamma plays a role in regulating the immune response of its target cell. A key signaling pathway that

2530-484: The secretion of IFNG by NK cells and Th1 cells, and it signals naive T helper cells (Th0) to differentiate into Th1 cells. The IFNG monomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region. This is shown in the structural models below. The α-helices in the core of the structure are numbered 1 to 6. The biologically active dimer is formed by anti-parallel inter-locking of

2585-426: The signal transduction of receptor tyrosine kinase pathways. SH2 domains contain about 100 amino acid residues and exhibit a central antiparallel β-sheet centered between two α-helices . Binding to phosphotyrosine -containing peptides involves a strictly-conserved Arg residue that pairs with the negatively-charged phosphate on the phosphotyrosine, and a surrounding pocket that recognizes flanking sequences on

2640-451: 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. 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

2695-692: The skin, effectively promoted hair growth. JAKs range from 120-140 kDa in size and have seven defined regions of homology called Janus homology domains 1 to 7 (JH1-7). JH1 is the kinase domain important for the enzymatic activity of the JAK and contains typical features of a tyrosine kinase such as conserved tyrosines necessary for JAK activation (e.g., Y1038/Y1039 in JAK1, Y1007/Y1008 in JAK2, Y980/Y981 in JAK3, and Y1054/Y1055 in Tyk2). Phosphorylation of these dual tyrosines leads to

2750-460: The target peptide. Compared to other signaling proteins, SH2 domains exhibit only a moderate degree of specificity for their target peptides, due to the relative weakness of the interactions with the flanking sequences. Over 100 human proteins are known to contain SH2 domains. A variety of tyrosine-containing sequences have been found to bind SH2 domains and are conserved across a wide range of organisms, performing similar functions. Binding of

2805-474: The treatment of atopic dermatitis and rheumatoid arthritis . They are also being studied in psoriasis , polycythemia vera , alopecia , essential thrombocythemia , ulcerative colitis , myeloid metaplasia with myelofibrosis and vitiligo . Examples are tofacitinib , baricitinib , upadacitinib and filgotinib . In 2014 researchers discovered that oral JAK inhibitors, when administered orally, could restore hair growth in some subjects and that applied to

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2860-511: 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. Interferon gamma has been shown to interact with Interferon gamma receptor 1 and Interferon gamma receptor 2 . Interferon gamma has been shown to be a crucial player in the immune response against some intracellular pathogens, including that of Chagas disease . It has also been identified as having

2915-495: The two monomers as shown below. In the cartoon model, one monomer is shown in red, the other in blue. Cellular responses to IFNG 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 genes (ISGs), including MHC II. IFNG also binds to

2970-432: The unglycosylated form that is expressed in E. coli . 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 cells , which are responsible for silencing immune responses against pathogens, preventing

3025-669: 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." The in 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 by apoptosis but sometimes by autophagy . In addition, it has been reported that mammalian glycosylation of recombinant human IFNG, expressed in HEK293 , improves its therapeutic efficacy compared to

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