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. 1996 Nov 1;184(5):1663–1669. doi: 10.1084/jem.184.5.1663

c-rel regulation of IL-2 gene expression may be mediated through activation of AP-1

PMCID: PMC2192877  PMID: 8920856

Abstract

T cell activation by antigen/MHC induces the expression of several genes critical to the immune response, including interleukin-2. T cells from mice deficient for the NF-kappa B family member c-rel cannot activate IL-2 gene expression. However, mutating the NF-kappa B site in the IL-2 promoter has only moderate effects. To investigate additional ways c-Rel could regulate IL-2 gene expression, we determined whether c- rel overexpression could increase the activity of other transcription factors involved in IL-2 promoter regulation: NF-AT, Oct/OAP (ARRE-1), and AP-1. In Jurkat TAg cells, overexpression of c-Rel increased AP-1 activation approximately 17-fold. Moreover, AP-1 activity stimulated by anti-TCR Abs or PMA/ionomycin was further increased by c-Rel overexpression. c-Rel overexpression did not affect NF-AT or ARRE-1 activity. Additionally, overexpression of c-Rel activated the nonconsensus AP-1 site from the IL-2 promoter (NF-IL-2B), although to a lesser extent, approximately sixfold. AP-1 activation required both the DNA binding and transactivation domains of c-Rel. Our results may provide an explanation for the effect on IL-2 gene activation in c-rel- deficient mice.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baeuerle P. A., Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. doi: 10.1146/annurev.iy.12.040194.001041. [DOI] [PubMed] [Google Scholar]
  2. Chen J., Stewart V., Spyrou G., Hilberg F., Wagner E. F., Alt F. W. Generation of normal T and B lymphocytes by c-jun deficient embryonic stem cells. Immunity. 1994 Apr;1(1):65–72. doi: 10.1016/1074-7613(94)90010-8. [DOI] [PubMed] [Google Scholar]
  3. Corcoran L. M., Karvelas M. Oct-2 is required early in T cell-independent B cell activation for G1 progression and for proliferation. Immunity. 1994 Nov;1(8):635–645. doi: 10.1016/1074-7613(94)90035-3. [DOI] [PubMed] [Google Scholar]
  4. Crabtree G. R., Clipstone N. A. Signal transmission between the plasma membrane and nucleus of T lymphocytes. Annu Rev Biochem. 1994;63:1045–1083. doi: 10.1146/annurev.bi.63.070194.005145. [DOI] [PubMed] [Google Scholar]
  5. Doerre S., Sista P., Sun S. C., Ballard D. W., Greene W. C. The c-rel protooncogene product represses NF-kappa B p65-mediated transcriptional activation of the long terminal repeat of type 1 human immunodeficiency virus. Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):1023–1027. doi: 10.1073/pnas.90.3.1023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Durand D. B., Shaw J. P., Bush M. R., Replogle R. E., Belagaje R., Crabtree G. R. Characterization of antigen receptor response elements within the interleukin-2 enhancer. Mol Cell Biol. 1988 Apr;8(4):1715–1724. doi: 10.1128/mcb.8.4.1715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fraser J. D., Straus D., Weiss A. Signal transduction events leading to T-cell lymphokine gene expression. Immunol Today. 1993 Jul;14(7):357–362. doi: 10.1016/0167-5699(93)90236-E. [DOI] [PubMed] [Google Scholar]
  8. Gerondakis S., Strasser A., Metcalf D., Grigoriadis G., Scheerlinck J. Y., Grumont R. J. Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3405–3409. doi: 10.1073/pnas.93.8.3405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ghosh G., van Duyne G., Ghosh S., Sigler P. B. Structure of NF-kappa B p50 homodimer bound to a kappa B site. Nature. 1995 Jan 26;373(6512):303–310. doi: 10.1038/373303a0. [DOI] [PubMed] [Google Scholar]
  10. Hodge M. R., Ranger A. M., Charles de la Brousse F., Hoey T., Grusby M. J., Glimcher L. H. Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice. Immunity. 1996 Apr;4(4):397–405. doi: 10.1016/s1074-7613(00)80253-8. [DOI] [PubMed] [Google Scholar]
  11. Hoyos B., Ballard D. W., Böhnlein E., Siekevitz M., Greene W. C. Kappa B-specific DNA binding proteins: role in the regulation of human interleukin-2 gene expression. Science. 1989 Apr 28;244(4903):457–460. doi: 10.1126/science.2497518. [DOI] [PubMed] [Google Scholar]
  12. Jain J., Loh C., Rao A. Transcriptional regulation of the IL-2 gene. Curr Opin Immunol. 1995 Jun;7(3):333–342. doi: 10.1016/0952-7915(95)80107-3. [DOI] [PubMed] [Google Scholar]
  13. Jain J., McCaffrey P. G., Miner Z., Kerppola T. K., Lambert J. N., Verdine G. L., Curran T., Rao A. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature. 1993 Sep 23;365(6444):352–355. doi: 10.1038/365352a0. [DOI] [PubMed] [Google Scholar]
  14. Jain J., McCaffrey P. G., Valge-Archer V. E., Rao A. Nuclear factor of activated T cells contains Fos and Jun. Nature. 1992 Apr 30;356(6372):801–804. doi: 10.1038/356801a0. [DOI] [PubMed] [Google Scholar]
  15. Jain J., Nalefski E. A., McCaffrey P. G., Johnson R. S., Spiegelman B. M., Papaioannou V., Rao A. Normal peripheral T-cell function in c-Fos-deficient mice. Mol Cell Biol. 1994 Mar;14(3):1566–1574. doi: 10.1128/mcb.14.3.1566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kamps M. P., Corcoran L., LeBowitz J. H., Baltimore D. The promoter of the human interleukin-2 gene contains two octamer-binding sites and is partially activated by the expression of Oct-2. Mol Cell Biol. 1990 Oct;10(10):5464–5472. doi: 10.1128/mcb.10.10.5464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kang S. M., Beverly B., Tran A. C., Brorson K., Schwartz R. H., Lenardo M. J. Transactivation by AP-1 is a molecular target of T cell clonal anergy. Science. 1992 Aug 21;257(5073):1134–1138. doi: 10.1126/science.257.5073.1134. [DOI] [PubMed] [Google Scholar]
  18. Kang S. M., Tran A. C., Grilli M., Lenardo M. J. NF-kappa B subunit regulation in nontransformed CD4+ T lymphocytes. Science. 1992 Jun 5;256(5062):1452–1456. doi: 10.1126/science.1604322. [DOI] [PubMed] [Google Scholar]
  19. Kumar S., Rabson A. B., Gélinas C. The RxxRxRxxC motif conserved in all Rel/kappa B proteins is essential for the DNA-binding activity and redox regulation of the v-Rel oncoprotein. Mol Cell Biol. 1992 Jul;12(7):3094–3106. doi: 10.1128/mcb.12.7.3094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Köntgen F., Grumont R. J., Strasser A., Metcalf D., Li R., Tarlinton D., Gerondakis S. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev. 1995 Aug 15;9(16):1965–1977. doi: 10.1101/gad.9.16.1965. [DOI] [PubMed] [Google Scholar]
  21. Lederer J. A., Liou J. S., Todd M. D., Glimcher L. H., Lichtman A. H. Regulation of cytokine gene expression in T helper cell subsets. J Immunol. 1994 Jan 1;152(1):77–86. [PubMed] [Google Scholar]
  22. Liou H. C., Baltimore D. Regulation of the NF-kappa B/rel transcription factor and I kappa B inhibitor system. Curr Opin Cell Biol. 1993 Jun;5(3):477–487. doi: 10.1016/0955-0674(93)90014-h. [DOI] [PubMed] [Google Scholar]
  23. Meyer C. F., Wang X., Chang C., Templeton D., Tan T. H. Interaction between c-Rel and the mitogen-activated protein kinase kinase kinase 1 signaling cascade in mediating kappaB enhancer activation. J Biol Chem. 1996 Apr 12;271(15):8971–8976. doi: 10.1074/jbc.271.15.8971. [DOI] [PubMed] [Google Scholar]
  24. Mueller D. L., Jenkins M. K. Molecular mechanisms underlying functional T-cell unresponsiveness. Curr Opin Immunol. 1995 Jun;7(3):375–381. doi: 10.1016/0952-7915(95)80113-8. [DOI] [PubMed] [Google Scholar]
  25. Northrop J. P., Ho S. N., Chen L., Thomas D. J., Timmerman L. A., Nolan G. P., Admon A., Crabtree G. R. NF-AT components define a family of transcription factors targeted in T-cell activation. Nature. 1994 Jun 9;369(6480):497–502. doi: 10.1038/369497a0. [DOI] [PubMed] [Google Scholar]
  26. Northrop J. P., Ullman K. S., Crabtree G. R. Characterization of the nuclear and cytoplasmic components of the lymphoid-specific nuclear factor of activated T cells (NF-AT) complex. J Biol Chem. 1993 Feb 5;268(4):2917–2923. [PubMed] [Google Scholar]
  27. Petrak D., Memon S. A., Birrer M. J., Ashwell J. D., Zacharchuk C. M. Dominant negative mutant of c-Jun inhibits NF-AT transcriptional activity and prevents IL-2 gene transcription. J Immunol. 1994 Sep 1;153(5):2046–2051. [PubMed] [Google Scholar]
  28. Schwartz R. H. A cell culture model for T lymphocyte clonal anergy. Science. 1990 Jun 15;248(4961):1349–1356. doi: 10.1126/science.2113314. [DOI] [PubMed] [Google Scholar]
  29. Sen R., Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986 Aug 29;46(5):705–716. doi: 10.1016/0092-8674(86)90346-6. [DOI] [PubMed] [Google Scholar]
  30. Serfling E., Avots A., Neumann M. The architecture of the interleukin-2 promoter: a reflection of T lymphocyte activation. Biochim Biophys Acta. 1995 Sep 19;1263(3):181–200. doi: 10.1016/0167-4781(95)00112-t. [DOI] [PubMed] [Google Scholar]
  31. Sha W. C., Liou H. C., Tuomanen E. I., Baltimore D. Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell. 1995 Jan 27;80(2):321–330. doi: 10.1016/0092-8674(95)90415-8. [DOI] [PubMed] [Google Scholar]
  32. Stein B., Baldwin A. S., Jr, Ballard D. W., Greene W. C., Angel P., Herrlich P. Cross-coupling of the NF-kappa B p65 and Fos/Jun transcription factors produces potentiated biological function. EMBO J. 1993 Oct;12(10):3879–3891. doi: 10.1002/j.1460-2075.1993.tb06066.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Su B., Jacinto E., Hibi M., Kallunki T., Karin M., Ben-Neriah Y. JNK is involved in signal integration during costimulation of T lymphocytes. Cell. 1994 Jun 3;77(5):727–736. doi: 10.1016/0092-8674(94)90056-6. [DOI] [PubMed] [Google Scholar]
  34. Thompson C. B., Wang C. Y., Ho I. C., Bohjanen P. R., Petryniak B., June C. H., Miesfeldt S., Zhang L., Nabel G. J., Karpinski B. cis-acting sequences required for inducible interleukin-2 enhancer function bind a novel Ets-related protein, Elf-1. Mol Cell Biol. 1992 Mar;12(3):1043–1053. doi: 10.1128/mcb.12.3.1043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ullman K. S., Northrop J. P., Admon A., Crabtree G. R. Jun family members are controlled by a calcium-regulated, cyclosporin A-sensitive signaling pathway in activated T lymphocytes. Genes Dev. 1993 Feb;7(2):188–196. doi: 10.1101/gad.7.2.188. [DOI] [PubMed] [Google Scholar]
  36. Umlauf S. W., Beverly B., Kang S. M., Brorson K., Tran A. C., Schwartz R. H. Molecular regulation of the IL-2 gene: rheostatic control of the immune system. Immunol Rev. 1993 Jun;133:177–197. doi: 10.1111/j.1600-065x.1993.tb01516.x. [DOI] [PubMed] [Google Scholar]
  37. Verma I. M., Stevenson J. K., Schwarz E. M., Van Antwerp D., Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev. 1995 Nov 15;9(22):2723–2735. doi: 10.1101/gad.9.22.2723. [DOI] [PubMed] [Google Scholar]
  38. Xanthoudakis S., Viola J. P., Shaw K. T., Luo C., Wallace J. D., Bozza P. T., Luk D. C., Curran T., Rao A. An enhanced immune response in mice lacking the transcription factor NFAT1. Science. 1996 May 10;272(5263):892–895. doi: 10.1126/science.272.5263.892. [DOI] [PubMed] [Google Scholar]
  39. Zhang L., Nabel G. J. Positive and negative regulation of IL-2 gene expression: role of multiple regulatory sites. Cytokine. 1994 May;6(3):221–228. doi: 10.1016/1043-4666(94)90016-7. [DOI] [PubMed] [Google Scholar]

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