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Regulation of IFN-γ Expression

  • John FenimoreEmail author
  • Howard A. Young
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 941)

Abstract

Interferon gamma, referred to here as IFN-γ, is a major component in immunological cell signaling and is a critical regulatory protein for overall immune system function. First discovered in 1965 (Wheelock Science 149: (3681)310–311, 1965), IFN-γ is the only Type II interferon identified. Its expression is both positively and negatively controlled by different factors. In this chapter, we will review the transcriptional and post-transcriptional control of IFN-γ expression. In the transcriptional control part, the regular activators and suppressors are summarized, we will also focus on the epigenetic control, such as chromosome access, DNA methylation, and histone acetylation. The more we learn about the control of this regulatory protein will allow us to apply this knowledge in the future to effectively manipulate IFN-γ expression for the treatment of infections, cancer, inflammation, and autoimmune diseases.

Keywords

IFN-γ Transcriptional control Epigenetic control LncRNA MicroRNA Activator Suppressor 

References

  1. 1.
    Wheelock EF. Interferon-like virus-inhibitor induced in human leukocytes by phytohemagglutinin. Science. 1965;149(3681):310–1.CrossRefGoogle Scholar
  2. 2.
    Naylor SL, Sakaguchi AY, Shows TB, Law ML, Goeddel DV, Gray PW. Human immune interferon gene is located on chromosome 12. J Exp Med. 1983;157(3):1020–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Naylor SL, Gray PW, Lalley PA. Mouse immune interferon (IFN-γ) gene is on chromosome 10. Somat Cell Mol Genet. 1984;10(5):531–4.PubMedCrossRefGoogle Scholar
  4. 4.
    Ushio S, Namba M, Okura T, Hattori K, Nukada Y, Akita K, Torigoe K, et al. Cloning of the cDNA for human IFN-gamma-inducing factor, expression in Escherichia coli, and studies on the biologic activities of the protein. J Immunol. 1996;156(11):4274–9.PubMedGoogle Scholar
  5. 5.
    Savan R, Ravichandran S, Collins JR, Sakai M, Young HA. Structural conservation of interferon gamma among vertebrates. Cytokine Growth Factor Rev. 2009;20(2):115–24.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Rusinova I, Forster S, Yu S, Kannan A, Masse M, Cumming H, Chapman R, Hertzog PJ. INTERFEROME v2. 0: an updated database of annotated interferon-regulated genes. Nucleic Acids Research. 2013 January; 41 (database issue): D1040-D1046. Smith NL, Dennings DW Clinical implications of interferon gamma genetic and epigenetic variants. Immunology 2014.Google Scholar
  7. 7.
    Kaufmann SH. Immunopathology of mycobacterial diseases. In Seminars in immunopathology (pp. 1–4). 2016. Berlin/Heidelberg: Springer.Google Scholar
  8. 8.
    Booty MG, Nunes-Alves C, Carpenter SM, Jayaraman P, Behar SM. Multiple inflammatory cytokines converge to regulate CD8+ T cell expansion and function during tuberculosis. J Immunol. 2016;169(4):1822–31.Google Scholar
  9. 9.
    Marciano BE, Wesley R, Ellen S, Anderson VL, Barnhart LA, Darnell D, Holland SM, et al. Long-term interferon-γ therapy for patients with chronic granulomatous disease. Clin Infect Dis. 2004;39(5):692–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol. 2007;96:41–101.PubMedCrossRefGoogle Scholar
  11. 11.
    Janeway CA, Travers P, Walport M, Shlomchik MJ. ImmunoBiology. 6th ed. New York: Garland Science Taylor and Francis Group; 2005.Google Scholar
  12. 12.
    Hirsch RL, Panitch HS, Johnson KP. Lymphocytes from multiple sclerosis patients produce elevated levels of gamma interferon in vitro. J Clin Immunol. 1985;5(6):386–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Sarvetnick N, Shizuru J, Liggitt D, Martin L, McIntyre B, Gregory A, et al. Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma. Nature. 1990;346:844–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Azar ST, Tamim H, Beyhum HN, Habbal MZ, Almawi WY. Type I (insulin-dependent) diabetes is a Th1-and Th2-mediated autoimmune disease. Clin Diagn Lab Immunol. 1999;6(3):306–10.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Collins PL, Chang S, Henderson M, Soutto M, Davis GM, McLoed AG, Aune TM, et al. Distal regions of the human IFNG locus direct cell type-specific expression. J Immunol. 2010;185(3):1492–501.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Eivazova ER, Aune TM. Dynamic alterations in the conformation of the Ifng gene region during T helper cell differentiation. Proc Natl Acad Sci. 2004;101(1):251–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Aune TM, Collins PL, Collier SP, Henderson MA, Chang S. Epigenetic activation and silencing of the gene that encodes IFN-γ. Front Immunol. 2013;4:112.Google Scholar
  18. 18.
    Chang S, Aune TM. Histone hyperacetylated domains across the Ifng gene region in natural killer cells and T cells. Proc Natl Acad Sci U S A. 2005;102:17095–100.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Schoenborn JR, Dorschner MO, Sekimata M, Santer DM, Shnyreva M, Fitzpatrick DR, et al. Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma. Nat Immunol. 2007;8:732–42.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Falek PR, Ben-Sasson SZ, Ariel M. Correlation between DNA methylation and murine IFN-γ and IL-4 expression. Cytokine. 2000;12(3):198–206.PubMedCrossRefGoogle Scholar
  21. 21.
    Phillips JE, Corces VG. CTCF: master weaver of the genome. Cell. 2009;137:1194–211.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Morinobu A, Gadina M, Strober W, Visconti R, Fornace A, Montagna C, O’Shea JJ, et al. STAT4 serine phosphorylation is critical for IL-12-induced IFN-γ production but not for cell proliferation. Proc Natl Acad Sci. 2002;99(19):12281–6.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, AzaBlanc P, et al. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science. 2005;309:1570–3.PubMedCrossRefGoogle Scholar
  24. 24.
    Vigneau S, Rohrlich PS, Brahic M, Bureau JF. Tmevpg1, a candidate gene for the control of Theiler’s virus persistence, could be implicated in the regulation of gamma interferon. J Virol. 2003;77:5632–8.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Muljo SA, Ansel KM, Kanellopoulou C, Livingston DM, Rao A, Rajewsky K. Aberrant T cell differentiation in the absence of Dicer. J Exp Med. 2005;202:261–9.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Dorhoi A, Iannaccone M, Farinacci M, Faé KC, Schreiber J, Moura-Alves P, … Kaufmann SHE. MicroRNA-223 controls susceptibility to tuberculosis by regulating lung neutrophil recruitment. The Journal of Clinical Investigation. 2013;123(11):4836–48. http://doi.org/10.1172/JCI67604.
  27. 27.
    Dai R, Phillips RA, Zhang Y, Khan D, Crasta O, Ahmed SA. Suppression of LPS-induced interferon-γ and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation. Blood. 2008;112(12):4591–7.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Park H, Huang X, Lu C, Cairo MS, Zhou X. MicroRNA-146a and microRNA-146b regulate human dendritic cell apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins. J Biol Chem. 2015;290(5):2831–41.PubMedCrossRefGoogle Scholar
  29. 29.
    Ma F, Xu S, Liu X, Zhang Q, Xu X, Liu M, Cao X, et al. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-[gamma]. Nat Immunol. 2011;12(9):861–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, Ansel KM, et al. MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells. Immunity. 2011;35(2):169–81.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Trotta R, Chen L, Ciarlariello D, Josyula S, Mao C, Costinean S, Caligiuri MA, et al. miR-155 regulates IFN-γ production in natural killer cells. Blood. 2012;119(15):3478–85.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261–74.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Kasahara TADASHI, Hooks JJ, Dougherty SF, Oppenheim JJ. Interleukin 2-mediated immune interferon (IFN-gamma) production by human T cells and T cell subsets. J Immunol. 1983;130(4):1784–9.PubMedGoogle Scholar
  34. 34.
    Hibbert L, Pflanz S, de Waal Malefyt R, Kastelein RA. IL-27 and IFN-α signal via Stat1 and Stat3 and induce T-Bet and IL-12R β 2 in naive T cells. J Interf Cytokine Res. 2003;23(9):513–22.CrossRefGoogle Scholar
  35. 35.
    Calarota SA, Otero M, Hermanstayne K, Lewis M, Rosati M, Felber BK, Weiner DB, et al. Use of interleukin 15 to enhance interferon-γ production by antigen-specific stimulated lymphocytes from rhesus macaques. J Immunol Methods. 2003;279(1):55–67.PubMedCrossRefGoogle Scholar
  36. 36.
    Biet F, Locht C, Kremer L. Immunoregulatory functions of interleukin 18 and its role in defense against bacterial pathogens. J Mol Med. 2002;80(3):147–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Bird JJ, Brown DR, Mullen AC, Moskowitz NH, Mahowald MA, Sider JR, Reiner SL, et al. Helper T cell differentiation is controlled by the cell cycle. Immunity. 1998;9(2):229–37.PubMedCrossRefGoogle Scholar
  38. 38.
    Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK, Gollapudi SK, et al. NetPath: a public resource of curated signal transduction pathways. Genome Biol. 2010;11(1):1–9.CrossRefGoogle Scholar
  39. 39.
    Strebovsky J, Walker P, Lang R, Dalpke AH. Suppressor of cytokine signaling 1 (SOCS1) limits NFkB signaling by decreasing p65 stability within the cell nucleus. FASEB J. 2011;25(3):863–74.PubMedCrossRefGoogle Scholar
  40. 40.
    Gonsky R, Deem RL, Bream J, Young HA, Targan SR. Enhancer role of STAT5 in CD2 activation of IFN-γ gene expression. J Immunol. 2004;173(10):6241–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Presky DH, Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, Gately MK, GublerA U. functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proc Natl Acad Sci U S A. 1996;93:14002–7.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Park WR, Nakahira M, Sugimoto N, Bian Y, Yashiro‐Ohtani Y, Zhou XY, Fujiwara H, et al. A mechanism underlying STAT4‐mediated up‐regulation of IFN‐y induction in TCR‐triggered T cells. Int Immunol. 2004;16(2):295–302.PubMedCrossRefGoogle Scholar
  43. 43.
    Ouyang W, Jacobson NG, Bhattacharya D, Gorham JD, Fenoglio D, Sha WC, Murphy KM, et al. The Ets transcription factor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. Proc Natl Acad Sci U S A. 1999;96(7):3888–93.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Afkarian M, Sedy JR, Yang J, Jacobson NG, Cereb N, Yang SY, Murphy KM, et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat Immunol. 2002;3(6):549–57.PubMedCrossRefGoogle Scholar
  45. 45.
    Hodge DL, Martinez A, Julias JG, Taylor Lynn S, Young HA. Regulation of nuclear gamma interferon gene expression by interleukin 12 (IL-12) and IL-2 represents a novel form of post transcriptional control. Mol Cell Biol. 2002;22(6):1742–53.Google Scholar
  46. 46.
    Cook KD, Miller J. TCR-dependent translational control of GATA-3 enhances Th2 differentiation. J Immunol. 2010;185(6):3209–16.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Gotthardt D, Putz EM, Straka E, Kudweis P, Biaggio M, Poli V, Sexl V, et al. Loss of STAT3 in murine NK cells enhances NK cell–dependent tumor surveillance. Blood. 2014;124(15):2370–9.PubMedCrossRefGoogle Scholar
  48. 48.
    Pensa S, Regis G, Boselli D, Novelli F, Poli V. STAT1 and STAT3 in tumorigenesis: two sides of the same coin? 2000.Google Scholar
  49. 49.
    Hoshino K, Tsutsui H, Kawai T, Takeda K, Nakanishi K, Takeda Y, Akira S. Cutting edge: generation of IL-18 receptor-deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding receptor. J Immunol. 1999;162(9):5041–4.PubMedGoogle Scholar
  50. 50.
    Kalina U, Kauschat D, Koyama N, Nuernberger H, Ballas K, Koschmieder S, Ottmann OG, et al. IL-18 activates STAT3 in the natural killer cell line 92, augments cytotoxic activity, and mediates IFN-γ production by the stress kinase p38 and by the extracellular regulated kinases p44erk-1 and p42erk-21. J Immunol. 2000;165(3):1307–13.PubMedCrossRefGoogle Scholar
  51. 51.
    Zarling S, Berenzon D, Dalai S, Liepinsh D, Steers N, Krzych U. The survival of memory CD8 T cells that is mediated by IL-15 correlates with sustained protection against malaria. J Immunol. 2013;190(10):5128–41.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Kumar A, Takada Y, Boriek AM, Aggarwal BB. Nuclear factor-kB: its role in health and disease. J Mol Med. 2004;82(7):434–48.PubMedCrossRefGoogle Scholar
  53. 53.
    Matikainen S, Paananen A, Miettinen M, Kurimoto M, Timonen T, Julkunen I, Sareneva T. IFN‐α and IL‐18 synergistically enhance IFN‐y production in human NK cells: differential regulation of Stat4 activation and IFN‐y gene expression by IFN‐α and IL‐12. Eur J Immunol. 2001;31(7):2236–45.PubMedCrossRefGoogle Scholar
  54. 54.
    de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, De Vries JE. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991;174(5):1209–20.PubMedCrossRefGoogle Scholar
  55. 55.
    Varma TK, Toliver-Kinsky TE, Lin CY, Koutrouvelis AP, Nichols JE, Sherwood ER. Cellular mechanisms that cause suppressed gamma interferon secretion in endotoxin-tolerant mice. Infect Immun. 2001;69(9):5249–63.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Egwuagu CE, Larkin III J. Therapeutic targeting of STAT pathways in CNS autoimmune diseases. JAK-STAT. 2013;2(1), e24134.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Schoenborn JR, Wilson CB. Regulation of interferon‐y during innate and adaptive immune responses. Adv Immunol. 2007;96:41–101.PubMedCrossRefGoogle Scholar
  58. 58.
    Eivazova ER, Markov SA, Pirozhkova I, Lipinski M, Vassetzky YS. Recruitment of RNA polymerase II in the Ifng gene promoter correlates with the nuclear matrix association in activated T helper cells. J Mol Biol. 2007;371(2):317–22.PubMedCrossRefGoogle Scholar
  59. 59.
    Knox JJ, Cosma GL, Betts MR, McLane LM. Characterization of T-bet and eomes in peripheral human immune cells. Front Immunol. 2014;5:217.Google Scholar
  60. 60.
    Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH. Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science (New York, NY). 2002;295(5553):338.CrossRefGoogle Scholar
  61. 61.
    Yang Y, Ochando JC, Bromberg JS, Ding Y. Identification of a distant T-bet enhancer responsive to IL-12/Stat4 and IFNγ/Stat1 signals. Blood. 2007;110(7):2494–500.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Hamilton SE, Jameson SC. CD8+ T cell differentiation: choosing a path through T-bet. Immunity. 2007;27(2):180–2.PubMedCrossRefGoogle Scholar
  63. 63.
    Gordon SM, Chaix J, Rupp LJ, Wu J, Madera S, Sun JC, Reiner SL, et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity. 2012;36(1):55–67.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Samten B, Townsend JC, Weis SE, Bhoumik A, Klucar P, Shams H, Barnes PF. CREB, ATF, and AP-1 transcription factors regulate IFN-γ secretion by human T cells in response to mycobacterial antigen. J Immunol. 2008;181(3):2056–64.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    MaciaÂn F, Lâopez-Rodrâiguez C, Rao A. Partners in transcription: NFAT and AP-1. Oncogene. 2001;20:2476–89.CrossRefGoogle Scholar
  66. 66.
    Hatton RD, Harrington LE, Luther RJ, Wakefield T, Janowski KM, Oliver JR, Weaver CT, et al. A distal conserved sequence element controls Ifng gene expression by T cells and NK cells. Immunity. 2006;25(5):717–29.PubMedCrossRefGoogle Scholar
  67. 67.
    Sica A, Dorman L, Viggiano V, Cippitelli M, Ghosh P, Rice N, Young HA. Interaction of NF-kB and NFAT with the interferon-γ promoter. J Biol Chem. 1997;272(48):30412–20.PubMedCrossRefGoogle Scholar
  68. 68.
    Wang L, Zhu J, Shan S, Qin Y, Kong Y, Liu J, Xie Y, et al. Repression of interferon-γ expression in T cells by Prospero-related homeobox protein. Cell Res. 2008;18(9):911–20.PubMedCrossRefGoogle Scholar
  69. 69.
    Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature. 1998;391(6662):79–82.PubMedCrossRefGoogle Scholar
  70. 70.
    Cunard R, Eto Y, Muljadi JT, Glass CK, Kelly CJ, Ricote M. Repression of IFN-gamma expression by peroxisome proliferator-activated receptor gamma. J Immunol. 2004;172:7530–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Waite KJ, Floyd ZE, Arbour-Reily P, Stephens JM. Interferon-γ-induced regulation of peroxisome proliferator-activated receptor γ and STATs in adipocytes. J Biol Chem. 2001;276(10):7062–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Dunn SE, Ousman SS, Sobel RA, Zuniga L, Baranzini SE, Youssef S, Steinman L, et al. Peroxisome proliferator–activated receptor (PPAR) α expression in T cells mediates gender differences in development of T cell–mediated autoimmunity. J Exp Med. 2007;204(2):321–30.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Lin JT, Martin SL, Xia L, Gorham JD. TGF-β1 uses distinct mechanisms to inhibit IFN-γ expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet. J Immunol. 2005;174(10):5950–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Yu J, Wei M, Becknell B, Trotta R, Liu S, Boyd Z, Mao H, et al. Pro-and antiinflammatory cytokine signaling: reciprocal antagonism regulates interferon-gamma production by human natural killer cells. Immunity. 2006;24(5):575–90.PubMedCrossRefGoogle Scholar
  75. 75.
    Savignac M, Pintado B, Gutierrez‐Adan A, Palczewska M, Mellström B, Naranjo JR. Transcriptional repressor DREAM regulates T‐lymphocyte proliferation and cytokine gene expression. EMBO J. 2005;24(20):3555–64.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Yagi R, Zhu J, Paul WE. An updated view on transcription factor GATA3-mediated regulation of Th1 and Th2 cell differentiation. Int Immunol. 2011;23(7):415–20.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Kim K, Kim N, Lee GR. Transcription factors Oct-1 and GATA-3 cooperatively regulate Th2 cytokine gene expression via the RHS5 within the Th2 locus control region. PLoS ONE. 2016;11(2), e0148576.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Kaminuma O, Kitamura F, Kitamura N, Miyagishi M, Taira K, Yamamoto K, Miyatake S, et al. GATA-3 suppresses IFN-γ promoter activity independently of binding to cis-regulatory elements. FEBS Lett. 2004;570(1):63–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Djuretic IM, Levanon D, Negreanu V, Groner Y, Rao A, Ansel KM. Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat Immunol. 2007;8(2):145–53.PubMedCrossRefGoogle Scholar
  80. 80.
    Penix L, Weaver WM, Pang Y, Young HA, Wilson CB. Two essential regulatory elements in the human interferon gamma promoter confer activation specific expression in T cells. J Exp Med. 1993;178(5):1483–96.PubMedCrossRefGoogle Scholar
  81. 81.
    Ye J, Cippitelli M, Dorman L, Ortaldo JR, Young HA. The nuclear factor YY1 suppresses the human gamma interferon promoter through two mechanisms: inhibition of AP1 binding and activation of a silencer element. Mol Cell Biol. 1996;16(9):4744–53.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Hodge DL, Berthet C, Coppola V, Kastenmüller W, Buschman MD, Schaughency PM, Ortaldo JR, et al. IFN-gamma AU-rich element removal promotes chronic IFN-gamma expression and autoimmunity in mice. J Autoimmun. 2014;53:33–45.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Ben-Asouli Y, Banai Y, Pel-Or Y, Shir A, Kaempfer R. Human interferon-gamma mRNA autoregulates its translation through a pseudoknot that activates the interferon-inducible protein kinase PKR. Cell. 2002;108(2):221–32.PubMedCrossRefGoogle Scholar
  84. 84.
    Williams BR. PKR; a sentinel kinase for cellular stress. Oncogene. 1999;18(45):6112–20.Google Scholar
  85. 85.
    Sareneva T, Cantell K, Pyhälä L, Pirhonen J, Julkunen I. Effect of carbohydrates on the pharmacokinetics of human interferon-γ. J Interf Res. 1993;13(4):267–9.CrossRefGoogle Scholar
  86. 86.
    Pesu M, Muul L, Kanno Y, O’Shea JJ. Proprotein convertase furin is preferentially expressed in T helper 1 cells and regulates interferon gamma. Blood. 2006;108:983–5.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  1. 1.National Cancer Institute at FrederickCancer and Inflammation Program, Center for Cancer ResearchFrederickUSA

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