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Interferon-gamma
From Wikipedia, the free encyclopedia
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Interferon-gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons.[1] This interferon was originally called macrophage-activating factor.
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[edit] Structure of IFN-γ
The IFN-γ monomer consists of a core of six α-helices and an extended unfolded sequence in the C-terminal region.[2][3] 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.
The structural models shown above (see PDB 1FG9) 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 the glycosaminoglycan heparan sulfate resides solely within the deleted sequence of 17 amino acids.[4]
[edit] 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-tumour properties.[5] It alters transcription in up to 30 genes producing a variety of physiological and cellular responses. Amongst the effects are:
- Increase antigen presentation of macrophages.
- Activate and increase lysosome activity in macrophages
- Suppress Th2 cell activity.
- Cause normal cells to increase expression of class I MHC molecules
- Promotes adhesion and binding required for leukocyte migration
- Promotes NK cell activity
Activation by IFN-γ is achieved by its interaction with a heterodimeric receptor consisting of IFNGR1 & IFNGR2 (interferon gamma receptors). IFN-γ binding to the receptor activates the JAK-STAT pathway. In addition, IFN-γ activates APCs and promotes Th1 differentiation by upregulating the transcription factor T-bet.
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.
[edit] Therapeutic uses
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Interferon-gamma
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| Systematic (IUPAC) name | |
| Human interferon gamma-1b | |
| Identifiers | |
| CAS number | 98059-61-1 |
| ATC code | L03 |
| PubChem | ? |
| DrugBank | |
| Chemical data | |
| Formula | C761H1206N214O225S6 |
| Mol. mass | 17145.6 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | ? |
| Half life | ? |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status | |
| Routes | ? |
Interferon gamma 1b is used to treat chronic granulomatous disease and osteopetrosis.
[edit] References
- ^ Gray PW, Goeddel DV (August 1982). "Structure of the human immune interferon gene". Nature 298 (5877): 859–63. doi:. PMID 6180322.
- ^ 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:. PMID 1902591.
- ^ Thiel DJ, le Du MH, Walter RL, et al (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:. PMID 10986460.
- ^ Vanhaverbeke C, Simorre JP, Sadir R, Gans P, Lortat-Jacob H (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:. PMID 15270718.
- ^ 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:. PMID 14525967.
[edit] 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. 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. 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:. PMID 15361241.
- Joseph AM, Kumar M, Mitra D (2005). "Nef: "necessary and enforcing factor" in HIV infection.". Curr. HIV Res. 3 (1): 87–94. PMID 15638726.
- Copeland KF (2006). "Modulation of HIV-1 transcription by cytokines and chemokines.". Mini reviews in medicinal chemistry 5 (12): 1093–101. 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:. PMID 16391178.
- Tellides G, Pober JS (2007). "Interferon-gamma axis in graft arteriosclerosis.". Circ. Res. 100 (5): 622–32. doi:. PMID 17363708.
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