Interferon-gamma

Interferon-gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons.cite journal | author = Gray PW, Goeddel DV | title = Structure of the human immune interferon gene | journal = Nature | volume = 298 | issue = 5877 | pages = 859–63 | year = 1982 | month = August | pmid = 6180322 | doi = 10.1038/298859a0 | url = | issn = ] This interferon was originally called macrophage-activating factor.

tructure 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.cite journal | author = Ealick SE, Cook WJ, Vijay-Kumar S, "et al" | title = Three-dimensional structure of recombinant human interferon-gamma | journal = Science (journal) | volume = 252 | issue = 5006 | pages = 698–702 | year = 1991 | month = May | pmid = 1902591 | doi = 10.1126/science.1902591 | url = | issn = ] cite journal | author = Thiel DJ, le Du MH, Walter RL, "et al" | title = Observation of an unexpected third receptor molecule in the crystal structure of human interferon-gamma receptor complex | journal = Structure | volume = 8 | issue = 9 | pages = 927–36 | year = 2000 | month = September | pmid = 10986460 | doi = 10.1016/S0969-2126(00)00184-2 | url = | issn = ] 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.cite journal | author = Vanhaverbeke C, Simorre JP, Sadir R, Gans P, Lortat-Jacob H | title = NMR characterization of the interaction between the C-terminal domain of interferon-gamma and heparin-derived oligosaccharides | journal = Biochem. J. | volume = 384 | issue = Pt 1 | pages = 93–9 | year = 2004 | month = November | pmid = 15270718 | pmc = 1134092 | doi = 10.1042/BJ20040757 | url = | issn = ]

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.cite journal | author = Schroder K, Hertzog PJ, Ravasi T, Hume DA | title = Interferon-gamma: an overview of signals, mechanisms and functions | journal = J. Leukoc. Biol. | volume = 75 | issue = 2 | pages = 163–89 | year = 2004 | month = February | pmid = 14525967 | doi = 10.1189/jlb.0603252 | url = | issn = ] 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 express class II 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.

Therapeutic uses

drugbox
IUPAC_name=Human interferon gamma-1b


CAS_number=82115-62-6
CAS_supplemental=98059-61-1
ATC_prefix=L03
ATC_suffix=AB03
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DrugBank=BTD00017
C=761 | H=1206 | N=214 | O=225 | S=6
molecular_weight=17145.6 g/mol
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routes_of_administration=Interferon gamma 1b is used to treat chronic granulomatous disease and osteopetrosis.

Scientists at the University of California at Berkeley have recently discovered that Diindolylmethane (DIM), a naturally occurring compound found in Brassica vegetables, upon oral consumption, is a direct and potent activator of Interferon-Gamma production and sensitivity within the body leading the way for the study of this compound as an anti-viral, anti-bacterial and anti-cancer therapeutic. As this is a dietary compound found in edible vegetables, this has caused a lot of excitement in the immunology field. This compound has also been shown to synergize with Interferon-Gamma in the expression and potentiation of the MHC-I Complex, leading to its study as a possible adjuvant to Interferon-gamma therapeutic models.

References

Further reading

*PBB_Further_reading
citations =
*cite journal | author=Ikeda H, Old LJ, Schreiber RD |title=The roles of IFN gamma in protection against tumor development and cancer immunoediting. |journal=Cytokine Growth Factor Rev. |volume=13 |issue= 2 |pages= 95–109 |year= 2002 |pmid= 11900986 |doi=
*cite journal | author=Chesler DA, Reiss CS |title=The role of IFN-gamma in immune responses to viral infections of the central nervous system. |journal=Cytokine Growth Factor Rev. |volume=13 |issue= 6 |pages= 441–54 |year= 2003 |pmid= 12401479 |doi=
*cite journal | author=Dessein A, Kouriba B, Eboumbou C, "et al." |title=Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in human schistosomiasis. |journal=Immunol. Rev. |volume=201 |issue= |pages= 180–90 |year= 2005 |pmid= 15361241 |doi= 10.1111/j.0105-2896.2004.00195.x
*cite journal | author=Joseph AM, Kumar M, Mitra D |title=Nef: "necessary and enforcing factor" in HIV infection. |journal=Curr. HIV Res. |volume=3 |issue= 1 |pages= 87–94 |year= 2005 |pmid= 15638726 |doi=
*cite journal | author=Copeland KF |title=Modulation of HIV-1 transcription by cytokines and chemokines. |journal=Mini reviews in medicinal chemistry |volume=5 |issue= 12 |pages= 1093–101 |year= 2006 |pmid= 16375755 |doi=
*cite journal | author=Chiba H, Kojima T, Osanai M, Sawada N |title=The significance of interferon-gamma-triggered internalization of tight-junction proteins in inflammatory bowel disease. |journal=Sci. STKE |volume=2006 |issue= 316 |pages= pe1 |year= 2006 |pmid= 16391178 |doi= 10.1126/stke.3162006pe1
*cite journal | author=Tellides G, Pober JS |title=Interferon-gamma axis in graft arteriosclerosis. |journal=Circ. Res. |volume=100 |issue= 5 |pages= 622–32 |year= 2007 |pmid= 17363708 |doi= 10.1161/01.RES.0000258861.72279.29

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