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Interferon, gamma

Line representation of the crystallographic structure of interferon gamma.[1]
Available structures
1eku, 1fg9, 1fyh, 1hig
Identifiers
Symbols IFNG; IFG; IFI
External IDs OMIM147570 MGI107656 HomoloGene55526 GeneCards: IFNG Gene
RNA expression pattern
PBB GE IFNG 210354 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3458 15978
Ensembl ENSG00000111537 ENSMUSG00000055170
UniProt P01579 Q6TDH0
RefSeq (mRNA) NM_000619 NM_008337
RefSeq (protein) NP_000610 NP_032363
Location (UCSC) Chr 12:
66.83 - 66.84 Mb
Chr 10:
117.84 - 117.85 Mb
PubMed search [1] [2]
Interferon-gamma
Systematic (IUPAC) name
Human interferon gamma-1b
Identifiers
CAS number 82115-62-6 98059-61-1
ATC code L03AB03
DrugBank BTD00017
Chemical data
Formula C761H1206N214O225S6 
Mol. mass 17145.6 g/mol
Therapeutic considerations
Pregnancy cat.  ?
Legal status

Interferon-gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons.[2] This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs. In humans, the IFN-γ protein is encoded by the IFNG gene.[3][4]

Contents

Function

IFN-γ, 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. Aberrant IFN-γ expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFN-γ in the immune system stems in part from its ability to inhibit viral replication directly, but, most important, derives from its immunostimulatory and immunomodulatory effects. IFN-γ is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 and CD8 cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops.[4][5]

Structure

The IFN-γ monomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region.[6][1] 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 a IFN-γ monomer.[1]

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 a IFN-γ dimer.[1]

Receptor binding

Figure 3. IFN dimer interacting with two IFNGR1 receptor molecules.[1]

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. 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.[7]

The structural models shown in figures 1-3 for IFN-γ[1] are all shortened at their C-termini by 17 amino acids. Full length IFN-γ is 143 amino acids in length, the models are 126 amino acids in length. Affinity for heparan sulfate resides solely within the deleted sequence of 17 amino acids.[8] 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.[9] In the absence of heparan sulfate the presence of the D1 sequence increases the rate at which IFN-γ-receptor complexes form.[7] Interactions between the D1 cluster of amino acids and the receptor may be the first step in complex formation. By binding to D1 HS may compete with the receptor and prevent active receptor complexes from forming.

The biological significance of heparan sulfates interaction with IFN-γ is unclear, however binding of the D1 cluster to HS may protect it from proteolytic cleavage.[9]

Biological activity

In contrast to interferon-α and interferon-β, which can be expressed by all cells, IFN-γ is secreted by Th1 cells, Tc cells, dendritic cells and NK cells. Also known as immune interferon, IFN-γ is the only Type II interferon. It is serologically distinct from Type I interferons and it is acid-labile, while the type I variants are acid-stable.

IFN-γ has antiviral, immunoregulatory, and anti-tumor properties.[10] It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Amongst the effects are:

IFN-γ is the hallmark cytokine of Th1 cells (whereas Th2 cells produce IL-4 and Th17 cells produce IL-17). NK cells and CD8+ cytotoxic T cells 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 NFκB.

Therapeutic use

Interferon gamma 1b is used to treat chronic granulomatous disease[11] and osteopetrosis.[12] It is manufactured by InterMune as Actimune® and costs around USD300 per vial.

Interactions

Interferon-gamma has been shown to interact with Interferon gamma receptor 1.[13][14]

Regulation

There is evidence that interferon-gamma expression is regulated by a pseudoknotted element in its 5' UTR.[15] There is also evidence that interferon-gamma is regulated either directly or indirectly by the microRNAs: miR-221, miR-155, miR-145 and miR-198.[16][17][18]

References

  1. ^ a b c d e f 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. 
  2. ^ Gray PW, Goeddel DV (August 1982). "Structure of the human immune interferon gene". Nature 298 (5877): 859–63. doi:10.1038/298859a0. PMID 6180322. 
  3. ^ 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.157.3.1020. PMID 6403645. 
  4. ^ a b "Entrez Gene: IFNGR2". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3460. 
  5. ^ 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. 
  6. ^ Ealick SE, Cook WJ, Vijay-Kumar S, et al. (May 1991). "Three-dimensional structure of recombinant human interferon-gamma". Science (journal) 252 (5006): 698–702. doi:10.1126/science.1902591. PMID 1902591. 
  7. ^ a b 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. 
  8. ^ 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. PMID 15270718. 
  9. ^ a b 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ Thiel, D J; le Du M H, Walter R L, D'Arcy A, Chène C, Fountoulakis M, Garotta G, Winkler F K, Ealick S E (Sep. 2000). "Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex". Structure (ENGLAND) 8 (9): 927–36. ISSN 0969-2126. PMID 10986460. 
  14. ^ Kotenko, S V; Izotova L S, Pollack B P, Mariano T M, Donnelly R J, Muthukumaran G, Cook J R, Garotta G, Silvennoinen O, Ihle J N (Sep. 1995). "Interaction between the components of the interferon gamma receptor complex". J. Biol. Chem. (UNITED STATES) 270 (36): 20915–21. ISSN 0021-9258. PMID 7673114. 
  15. ^ 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: 221–232. doi:10.1016/S0092-8674(02)00616-5. PMID 11832212. 
  16. ^ Hu G, Gong AY, Liu J, Zhou R, Deng C, Chen XM (2010). "miR-221 suppresses ICAM-1 translation and regulates interferon-gamma-induced ICAM-1 expression in human cholangiocytes.". Am J Physiol Gastrointest Liver Physiol. PMID 20110463. 
  17. ^ Banerjee A, Schambach F, DeJong CS, Hammond SM, Reiner SL (2010). "Micro-RNA-155 inhibits IFN-gamma signaling in CD4+ T cells.". Eur J Immunol 40 (1): 225-31. PMID 19877012. 
  18. ^ 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. PMID 18061676. 

Further reading

  • 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. 

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


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