Line representation of the crystallographic structure of interferon gamma.
|Symbols||; IFG; IFI|
|RNA expression pattern|
Crystal structure of a biologically active single chain mutant of human interferon gamma
|Systematic (IUPAC) name|
|Human interferon gamma-1b|
|Mol. mass||17145.6 g/mol|
|(what is this?)|
Interferon gamma (IFNγ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was recognized when human blood lymphocytes or mouse peritoneal lymphocytes obtained from tuberculin-sensitized individuals were challenged with PPD and 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. This interferon was later called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFNγ belongs. In humans, the IFNγ protein is encoded by the IFNG gene.
IFNγ, or type II interferon, is a cytokine that is critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. IFNγ is an important activator of macrophages. Aberrant IFNγ expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFNγ in the immune system stems in part from its ability to inhibit viral replication directly, and most importantly from its immunostimulatory and immunomodulatory effects. IFNγ is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 Th1 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops.
The IFNγ monomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region. This is shown in the structural models below. The α-helices in the core of the structure are numbered 1 to 6.
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.
Cellular responses to IFNγ are activated through its interaction with a heterodimeric receptor consisting of Interferon gamma receptor 1 (IFNGR1) and Interferon gamma receptor 2 (IFNGR2). IFNγ binding to the receptor activates the JAK-STAT pathway. IFNγ also binds to the glycosaminoglycan heparan sulfate (HS) at the cell surface. However, in contrast to many other heparan sulfate binding proteins, where binding promotes biological activity, the binding of IFNγ to HS inhibits its biological activity.
The structural models shown in figures 1-3 for IFNγ are all shortened at their C-termini by 17 amino acids. Full length IFNγ is 143 amino acids long, the models are 126 amino acids long. Affinity for heparan sulfate resides solely within the deleted sequence of 17 amino acids. Within this sequence of 17 amino acids lie two clusters of basic amino acids termed D1 and D2, respectively. Heparan sulfate interacts with both of these clusters. In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFNγ-receptor complexes form. Interactions between the D1 cluster of amino acids and the receptor may be the first step in complex formation. By binding to D1 HS may compete with the receptor and prevent active receptor complexes from forming.
It was believed earlier that IFNγ is secreted by T helper cells (specifically, Th1 cells), cytotoxic T cells (TC cells) and NK cells only. But later studies showed that myeloid cells, dendritic cells and macrophages in particular, also secrete IFNγ that is likely important for cell self activation during the onset of the infection. Also, IFNγ is the only Type II interferon, and it is serologically distinct from Type I interferons: it is acid-labile, while the type I variants are acid-stable.
IFNγ has antiviral, immunoregulatory, and anti-tumor properties. It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Among the effects are:
- Promotes NK cell activity
- Increase antigen presentation and lysosome activity of macrophages.
- Activate inducible Nitric Oxide Synthase iNOS
- Induces the production of IgG2a and IgG3 from activated plasma B cells
- Promotes Th1 differentiation by upregulating the transcription factor T-bet, ultimately leading to cellular immunity: cytotoxic CD8+ T-cells and macrophage activity - while suppressing Th2 differentiation, which would cause a humoral (antibody) response
- Cause normal cells to increase expression of class I MHC molecules as well as class II MHC on antigen-presenting cells—to be specific, through induction of antigen processing genes, including subunits of the immunoproteasome (MECL1, LMP2, LMP7), as well as TAP and ERAAP in addition possibly to the direct upregulation of MHC heavy chains and B2-microglobulin itself
- Promotes adhesion and binding required for leukocyte migration
- Induces the expression of intrinsic defense factors—for example, with respect to retroviruses, relevant genes include TRIM5alpha, APOBEC, and Tetherin, representing directly antiviral effects
IFNγ is the primary cytokine that defines Th1 cells: Th1 cells secrete IFNγ, which in turn causes more undifferentiated CD4+ cells (Th0 cells) to differentiate into Th1 cells, representing a positive feedback loop—while suppressing Th2 cell differentiation. (Equivalent defining cytokines for other cells include IL-4 for Th2 cells and IL-17 for Th17 cells.)
NK cells and CD8+ cytotoxic T cells also produce IFNγ. IFNγ suppresses osteoclast formation by rapidly degrading the RANK adaptor protein TRAF6 in the RANK-RANKL signaling pathway, which otherwise stimulates the production of NF-κB.
Activity in Granuloma Formation
A granuloma is the body's way of dealing with a substance it cannot remove or sterilize. Infectious causes of granulomas (infections are typically the most common cause of granulomas) include tuberculosis, leprosy, histoplasmosis, cryptococcosis, coccidioidomycosis, blastomycosis, and cat scratch disease. Examples of non-infectious granulomatous diseases are sarcoidosis, Crohn's disease, berylliosis, giant-cell arteritis, Wegener's granulomatosis, Churg-Strauss syndrome, pulmonary rheumatoid nodules, and aspiration of food and other particulate material into the lung. The infectious pathophysiology of granulomas is discussed primarily here.
The key association between interferon-γ and granulomas is that interferon-γ activates macrophages so that they become more powerful in killing intracellular organisms. Activation of macrophages by Th1 helper cell's hallmark cytokine interferon-γ in mycobacterial infections, allows the macrophages to overcome the inhibition of phagolysosome maturation caused by mycobacteria (to stay alive inside macrophages). So the first step is the activation of Th1 helper cells by macrophages releasing IL-1 and IL-12 in the presence of intracellular pathogens, as well as the presentation of some of antigens in MHC class II surface protein. Next the Th1 helper cells aggregate around the macrophages and release interferon-γ, which causes the activation of macrophages. Further activation of macrophages causes a cycle of further killing of intracellular bacteria, further presentation of antigens to Th1 helper cells with further release of interferon-γ. Finally, macrophages surround the Th1 helper cells and become fibroblast-like cells further walling off the infection.
Activity during pregnancy
Uterine Natural Killer cells (NK) secrete high levels of chemoattractants, such as IFNγ. IFNγ dilates and thins the walls of maternal spiral arteries to enhance blood flow to the implantation site. This remodeling aids in the development of the placenta as it invades the uterus in its quest for nutrients. IFNγ knockout mice fail to initiate normal pregnancy-induced modification of decidual arteries. These models display abnormally low amounts of cells or necrosis of decidua.
It was not approved to treat idiopathic pulmonary fibrosis (IPF). In 2002, the manufacturer InterMune issued a press release saying that phase III data demonstrated survival benefit in IPF and reduced mortality by 70% in patients with mild to moderate disease. The U.S. Department of Justice charged that the release contained false and misleading statements. InterMune's chief executive, Scott Harkonen, was accused of manipulating the trial data, was convicted in 2009 of wire fraud, and was sentenced to fines and community service. Harkonen appealed his conviction to the U.S. Court of Appeals for the Ninth Circuit, and lost.
It is manufactured by InterMune as Actimmune and costs around USD300 per vial.
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.
- PDB 1FG9; Thiel DJ, le Du MH, Walter RL, D'Arcy A, Chène C, Fountoulakis M, Garotta G, Winkler FK, Ealick SE (September 2000). "Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex". Structure 8 (9): 927–36. doi:10.1016/S0969-2126(00)00184-2. PMID 10986460.
- Gray PW, Goeddel DV (August 1982). "Structure of the human immune interferon gene". Nature 298 (5877): 859–63. doi:10.1038/298859a0. PMID 6180322.
- Green JA, Cooperband SR, Kibrick S (1969). "Immune specific induction of interferon production in cultures of human blood lymphocytes". Science 164: 1415–1417. PMID 5783715.
- Milstone, LM; Waksman BH (1970). "Release of virus inhibitor from tuberculin-sensitized peritoneal cells stimulated by antigen". J Immunol 105: 1068–1071. PMID 4321289.
- Naylor SL, Sakaguchi AY, Shows TB, Law ML, Goeddel DV, Gray PW (March 1983). "Human immune interferon gene is located on chromosome 12". J. Exp. Med. 157 (3): 1020–7. doi:10.1084/jem.157..1020. PMC 2186972. PMID 6403645.
- "Entrez Gene: IFNGR2".
- Schoenborn JR, Wilson CB (2007). "Regulation of interferon-gamma during innate and adaptive immune responses". Adv. Immunol. 96: 41–101. doi:10.1016/S0065-2776(07)96002-2. PMID 17981204.
- Ealick SE, Cook WJ, Vijay-Kumar S, et al. (May 1991). "Three-dimensional structure of recombinant human interferon-gamma". Science 252 (5006): 698–702. doi:10.1126/science.1902591. PMID 1902591.
- Sadir R, Forest E, Lortat-Jacob H. (May 1998). "The heparan sulfate binding sequence of interferon-gamma increased the on rate of the interferon-gamma-interferon-gamma receptor complex formation". J. Biol. Chem. 273 (18): 10919–10925. doi:10.1074/jbc.273.18.10919. PMID 9556569.
- Vanhaverbeke C, Simorre JP, et al. (November 2004). "NMR characterization of the interaction between the C-terminal domain of interferon-gamma and heparin-derived oligosaccharides". Biochem. J. 384 (Pt 1): 93–9. doi:10.1042/BJ20040757. PMC 1134092. PMID 15270718.
- Lortat-Jacob H, Grimaud JA (March 1991). "Interferon-gamma binds to heparan sulfate by a cluster of amino acids located in the C-terminal part of the molecule". FEBS Lett. 280 (1): 152–154. doi:10.1016/0014-5793(91)80225-R. PMID 1901275.
- Schroder K, Hertzog PJ, Ravasi T, Hume DA (February 2004). "Interferon-gamma: an overview of signals, mechanisms and functions". J. Leukoc. Biol. 75 (2): 163–89. doi:10.1189/jlb.0603252. PMID 14525967.
- Citations needed
- Ashkar AA, Di Santo JP, Croy BA (July 2000). "Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy". J. Exp. Med. 192 (2): 259–70. doi:10.1084/jem.192.2.259. PMC 2193246. PMID 10899912.
- Todd PA, Goa KL (January 1992). "Interferon gamma-1b. A review of its pharmacology and therapeutic potential in chronic granulomatous disease". Drugs 43 (1): 111–22. PMID 1372855.
- Key LL, Ries WL, Rodriguiz RM, Hatcher HC (July 1992). "Recombinant human interferon gamma therapy for osteopetrosis". J. Pediatr. 121 (1): 119–24. doi:10.1016/S0022-3476(05)82557-0. PMID 1320672.
- Silverman E (September 2013). "The line between scientific uncertainty and promotion of snake oil". BMJ 347: f5687–f5687. doi:10.1136/bmj.f5687.
- "Open-label pilot study of interferon gamma-1b (Actimmune™) for the treatment of Friedreich Ataxia". FARA. 10 June 2013. Retrieved 4 October 2013.
- Thiel DJ, le Du MH, Walter RL, D'Arcy A, Chène C, Fountoulakis M, Garotta G, Winkler FK, Ealick SE (September 2000). "Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex". Structure 8 (9): 927–36. doi:10.1016/S0969-2126(00)00184-2. PMID 10986460.
- Kotenko SV, Izotova LS, Pollack BP, Mariano TM, Donnelly RJ, Muthukumaran G, Cook JR, Garotta G, Silvennoinen O, Ihle JN (September 1995). "Interaction between the components of the interferon gamma receptor complex". J. Biol. Chem. 270 (36): 20915–21. doi:10.1074/jbc.270.36.20915. PMID 7673114.
- Ben-Asouli, Y; Banai Y, Pel-Or Y, Shir A, Kaempfer R (2002). "Human interferon-gamma mRNA autoregulates its translation through a pseudoknot that activates the interferon-inducible protein kinase PKR". Cell 108 (2): 221–232. doi:10.1016/S0092-8674(02)00616-5. PMID 11832212.
- Asirvatham AJ, Gregorie CJ, Hu Z, Magner WJ, Tomasi TB (2008). "MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components.". Mol Immunol 45 (7): 1995–2006. doi:10.1016/j.molimm.2007.10.035. PMC 2678893. PMID 18061676.
- Hall, Stephen K. (1997). A commotion in the blood: life, death, and the immune system. New York: Henry Holt. ISBN 0-8050-5841-9.
- Ikeda H, Old LJ, Schreiber RD (2002). "The roles of IFN gamma in protection against tumor development and cancer immunoediting.". Cytokine Growth Factor Rev. 13 (2): 95–109. doi:10.1016/S1359-6101(01)00038-7. PMID 11900986.
- Chesler DA, Reiss CS (2003). "The role of IFN-gamma in immune responses to viral infections of the central nervous system.". Cytokine Growth Factor Rev. 13 (6): 441–54. doi:10.1016/S1359-6101(02)00044-8. PMID 12401479.
- Dessein A, Kouriba B, Eboumbou C, et al. (2005). "Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in human schistosomiasis.". Immunol. Rev. 201: 180–90. doi:10.1111/j.0105-2896.2004.00195.x. PMID 15361241.
- Joseph AM, Kumar M, Mitra D (2005). "Nef: "necessary and enforcing factor" in HIV infection.". Curr. HIV Res. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.
- Copeland KF (2006). "Modulation of HIV-1 transcription by cytokines and chemokines.". Mini reviews in medicinal chemistry 5 (12): 1093–101. doi:10.2174/138955705774933383. PMID 16375755.
- Chiba H, Kojima T, Osanai M, Sawada N (2006). "The significance of interferon-gamma-triggered internalization of tight-junction proteins in inflammatory bowel disease.". Sci. STKE 2006 (316): pe1. doi:10.1126/stke.3162006pe1. PMID 16391178.
- Tellides G, Pober JS (2007). "Interferon-gamma axis in graft arteriosclerosis.". Circ. Res. 100 (5): 622–32. doi:10.1161/01.RES.0000258861.72279.29. PMID 17363708.