Interferon-gamma

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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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 protein data bank code 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 sulphate resides solely within the deleted sequence of 17 amino acids.^[4]

Biological activity

In contrast to interferon-α and interferon-β which can be expressed by all cells, IFN-γ is secreted by T lymphocytes and NK cells only. 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. 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 (Th2 cells produce IL-4). 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

Interferons are used to treat infectious diseases and cancer.

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

1. ^ Gray, P. W. and Goeddel, D. V. (1982). "Structure of the human immune interferon gene". Nature 298: 859-863.
2. ^ Ealick, S. E., Cook, W. J. et al. (1991). "Three-dimensional structure of recombinant human interferon-gamma". Science 252: 698-702.
3. ^ Thiel, D. J. et al. (2000). "Observation of an unexpected third receptor molecule in the crystal structure of human interferon-γ receptor complex". Structure 8 (9): 927-936.
4. ^ Vanhaverbeke, C. Simorre, J-P. et al. (2004). "NMR characterization of the interaction between the C-terminal domain of interferon-γ and heparin-derived oligosaccharides" 384: 93-99.
5. ^ Schroder et al. (2004). "Interferon-γ an overview of signals, mechanisms and functions". Journal of Leukocyte Biology 75: 163-189.

Further reading