Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1999 Jan 15;18(2):420–432. doi: 10.1093/emboj/18.2.420

Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation.

B Li 1, C Tournier 1, R J Davis 1, R A Flavell 1
PMCID: PMC1171136  PMID: 9889198

Abstract

The molecular basis for restricted cytokine expression by T helper 1 (Th1) and T helper 2 (Th2) cells is unclear. Previous studies found that P1, an element of the interleukin 4 (IL-4) promoter that binds AP-1, is important for Th2-restricted IL-4 expression. Here we show that JunB, but not the other Jun family members, was selectively induced in Th2 cells and not in Th1 cells during differentiation. JunB has previously been considered to be a negative regulator of transcription. However, we show that JunB binds directly to the P1 site and synergizes with c-Maf to activate an IL-4 luciferase reporter gene. JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation. In transgenic mice, elevated JunB levels caused increased expression of several Th2 cytokines in developing Th1 cells. JunB also upregulated IL-4 expression in response to immunization. Thus, the early increase of JunB protein in Th2 cells can provide the specificity for c-Maf in IL-4 expression during T cell development and directs thereby Th2 differentiation.

Full Text

The Full Text of this article is available as a PDF (558.8 KB).

Selected References

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

  1. Abbas A. K., Murphy K. M., Sher A. Functional diversity of helper T lymphocytes. Nature. 1996 Oct 31;383(6603):787–793. doi: 10.1038/383787a0. [DOI] [PubMed] [Google Scholar]
  2. Abe E., De Waal Malefyt R., Matsuda I., Arai K., Arai N. An 11-base-pair DNA sequence motif apparently unique to the human interleukin 4 gene confers responsiveness to T-cell activation signals. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2864–2868. doi: 10.1073/pnas.89.7.2864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alvarez E., Northwood I. C., Gonzalez F. A., Latour D. A., Seth A., Abate C., Curran T., Davis R. J. Pro-Leu-Ser/Thr-Pro is a consensus primary sequence for substrate protein phosphorylation. Characterization of the phosphorylation of c-myc and c-jun proteins by an epidermal growth factor receptor threonine 669 protein kinase. J Biol Chem. 1991 Aug 15;266(23):15277–15285. [PubMed] [Google Scholar]
  4. Aune T. M., Flavell R. A. Differential expression of transcription directed by a discrete NF-AT binding element from the IL-4 promoter in naive and effector CD4 T cells. J Immunol. 1997 Jul 1;159(1):36–43. [PubMed] [Google Scholar]
  5. Bruhn K. W., Nelms K., Boulay J. L., Paul W. E., Lenardo M. J. Molecular dissection of the mouse interleukin-4 promoter. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9707–9711. doi: 10.1073/pnas.90.20.9707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chiu R., Angel P., Karin M. Jun-B differs in its biological properties from, and is a negative regulator of, c-Jun. Cell. 1989 Dec 22;59(6):979–986. doi: 10.1016/0092-8674(89)90754-x. [DOI] [PubMed] [Google Scholar]
  7. Chuvpilo S., Schomberg C., Gerwig R., Heinfling A., Reeves R., Grummt F., Serfling E. Multiple closely-linked NFAT/octamer and HMG I(Y) binding sites are part of the interleukin-4 promoter. Nucleic Acids Res. 1993 Dec 11;21(24):5694–5704. doi: 10.1093/nar/21.24.5694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Constant S. L., Bottomly K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol. 1997;15:297–322. doi: 10.1146/annurev.immunol.15.1.297. [DOI] [PubMed] [Google Scholar]
  9. Davis R. J., Czech M. P. Tumor-promoting phorbol diesters cause the phosphorylation of epidermal growth factor receptors in normal human fibroblasts at threonine-654. Proc Natl Acad Sci U S A. 1985 Apr;82(7):1974–1978. doi: 10.1073/pnas.82.7.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Davydov I. V., Krammer P. H., Li-Weber M. Nuclear factor-IL6 activates the human IL-4 promoter in T cells. J Immunol. 1995 Dec 1;155(11):5273–5279. [PubMed] [Google Scholar]
  11. Dickens M., Rogers J. S., Cavanagh J., Raitano A., Xia Z., Halpern J. R., Greenberg M. E., Sawyers C. L., Davis R. J. A cytoplasmic inhibitor of the JNK signal transduction pathway. Science. 1997 Aug 1;277(5326):693–696. doi: 10.1126/science.277.5326.693. [DOI] [PubMed] [Google Scholar]
  12. Dérijard B., Hibi M., Wu I. H., Barrett T., Su B., Deng T., Karin M., Davis R. J. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell. 1994 Mar 25;76(6):1025–1037. doi: 10.1016/0092-8674(94)90380-8. [DOI] [PubMed] [Google Scholar]
  13. Gupta S., Barrett T., Whitmarsh A. J., Cavanagh J., Sluss H. K., Dérijard B., Davis R. J. Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J. 1996 Jun 3;15(11):2760–2770. [PMC free article] [PubMed] [Google Scholar]
  14. Gupta S., Campbell D., Dérijard B., Davis R. J. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995 Jan 20;267(5196):389–393. doi: 10.1126/science.7824938. [DOI] [PubMed] [Google Scholar]
  15. Ho I. C., Hodge M. R., Rooney J. W., Glimcher L. H. The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4. Cell. 1996 Jun 28;85(7):973–983. doi: 10.1016/s0092-8674(00)81299-4. [DOI] [PubMed] [Google Scholar]
  16. Ho S. N., Hunt H. D., Horton R. M., Pullen J. K., Pease L. R. Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene. 1989 Apr 15;77(1):51–59. doi: 10.1016/0378-1119(89)90358-2. [DOI] [PubMed] [Google Scholar]
  17. Hsieh C. S., Heimberger A. B., Gold J. S., O'Garra A., Murphy K. M. Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system. Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6065–6069. doi: 10.1073/pnas.89.13.6065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  19. Ip Y. T., Davis R. J. Signal transduction by the c-Jun N-terminal kinase (JNK)--from inflammation to development. Curr Opin Cell Biol. 1998 Apr;10(2):205–219. doi: 10.1016/s0955-0674(98)80143-9. [DOI] [PubMed] [Google Scholar]
  20. Kallunki T., Deng T., Hibi M., Karin M. c-Jun can recruit JNK to phosphorylate dimerization partners via specific docking interactions. Cell. 1996 Nov 29;87(5):929–939. doi: 10.1016/s0092-8674(00)81999-6. [DOI] [PubMed] [Google Scholar]
  21. Kamogawa Y., Minasi L. A., Carding S. R., Bottomly K., Flavell R. A. The relationship of IL-4- and IFN gamma-producing T cells studied by lineage ablation of IL-4-producing cells. Cell. 1993 Dec 3;75(5):985–995. doi: 10.1016/0092-8674(93)90542-x. [DOI] [PubMed] [Google Scholar]
  22. Kerppola T. K., Curran T. Maf and Nrl can bind to AP-1 sites and form heterodimers with Fos and Jun. Oncogene. 1994 Mar;9(3):675–684. [PubMed] [Google Scholar]
  23. Killeen N., Sawada S., Littman D. R. Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4. EMBO J. 1993 Apr;12(4):1547–1553. doi: 10.1002/j.1460-2075.1993.tb05798.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Li-Weber M., Eder A., Krafft-Czepa H., Krammer P. H. T cell-specific negative regulation of transcription of the human cytokine IL-4. J Immunol. 1992 Mar 15;148(6):1913–1918. [PubMed] [Google Scholar]
  25. Manetti R., Parronchi P., Giudizi M. G., Piccinni M. P., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  27. Paul W. E., Seder R. A. Lymphocyte responses and cytokines. Cell. 1994 Jan 28;76(2):241–251. doi: 10.1016/0092-8674(94)90332-8. [DOI] [PubMed] [Google Scholar]
  28. Rana A., Gallo K., Godowski P., Hirai S., Ohno S., Zon L., Kyriakis J. M., Avruch J. The mixed lineage kinase SPRK phosphorylates and activates the stress-activated protein kinase activator, SEK-1. J Biol Chem. 1996 Aug 9;271(32):19025–19028. doi: 10.1074/jbc.271.32.19025. [DOI] [PubMed] [Google Scholar]
  29. Reiner S. L., Zheng S., Corry D. B., Locksley R. M. Constructing polycompetitor cDNAs for quantitative PCR (J. Immunol. Methods 165 (1993) 37-46; 173(1994) 133). J Immunol Methods. 1994 Oct 14;175(2):275–275. doi: 10.1016/0022-1759(94)90370-0. [DOI] [PubMed] [Google Scholar]
  30. Rincón M., Dérijard B., Chow C. W., Davis R. J., Flavell R. A. Reprogramming the signalling requirement for AP-1 (activator protein-1) activation during differentiation of precursor CD4+ T-cells into effector Th1 and Th2 cells. Genes Funct. 1997 Feb;1(1):51–68. doi: 10.1046/j.1365-4624.1997.00007.x. [DOI] [PubMed] [Google Scholar]
  31. Rincón M., Flavell R. A. Transcription mediated by NFAT is highly inducible in effector CD4+ T helper 2 (Th2) cells but not in Th1 cells. Mol Cell Biol. 1997 Mar;17(3):1522–1534. doi: 10.1128/mcb.17.3.1522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Robinson M. J., Cobb M. H. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997 Apr;9(2):180–186. doi: 10.1016/s0955-0674(97)80061-0. [DOI] [PubMed] [Google Scholar]
  33. Romagnani S. The Th1/Th2 paradigm. Immunol Today. 1997 Jun;18(6):263–266. doi: 10.1016/s0167-5699(97)80019-9. [DOI] [PubMed] [Google Scholar]
  34. Rooney J. W., Hodge M. R., McCaffrey P. G., Rao A., Glimcher L. H. A common factor regulates both Th1- and Th2-specific cytokine gene expression. EMBO J. 1994 Feb 1;13(3):625–633. doi: 10.1002/j.1460-2075.1994.tb06300.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Rooney J. W., Hoey T., Glimcher L. H. Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene. Immunity. 1995 May;2(5):473–483. doi: 10.1016/1074-7613(95)90028-4. [DOI] [PubMed] [Google Scholar]
  36. Schreiber E., Matthias P., Müller M. M., Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. doi: 10.1093/nar/17.15.6419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schütte J., Viallet J., Nau M., Segal S., Fedorko J., Minna J. jun-B inhibits and c-fos stimulates the transforming and trans-activating activities of c-jun. Cell. 1989 Dec 22;59(6):987–997. doi: 10.1016/0092-8674(89)90755-1. [DOI] [PubMed] [Google Scholar]
  38. Seder R. A., Gazzinelli R., Sher A., Paul W. E. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10188–10192. doi: 10.1073/pnas.90.21.10188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Seder R. A., Paul W. E., Davis M. M., Fazekas de St Groth B. The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med. 1992 Oct 1;176(4):1091–1098. doi: 10.1084/jem.176.4.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Smith D. B., Johnson K. S. Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene. 1988 Jul 15;67(1):31–40. doi: 10.1016/0378-1119(88)90005-4. [DOI] [PubMed] [Google Scholar]
  41. Swain S. L. IL4 dictates T-cell differentiation. Res Immunol. 1993 Oct;144(8):616–620. doi: 10.1016/s0923-2494(05)80013-6. [DOI] [PubMed] [Google Scholar]
  42. Szabo S. J., Gold J. S., Murphy T. L., Murphy K. M. Identification of cis-acting regulatory elements controlling interleukin-4 gene expression in T cells: roles for NF-Y and NF-ATc. Mol Cell Biol. 1993 Aug;13(8):4793–4805. doi: 10.1128/mcb.13.8.4793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tibbles L. A., Ing Y. L., Kiefer F., Chan J., Iscove N., Woodgett J. R., Lassam N. J. MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. EMBO J. 1996 Dec 16;15(24):7026–7035. [PMC free article] [PubMed] [Google Scholar]
  44. Todd M. D., Grusby M. J., Lederer J. A., Lacy E., Lichtman A. H., Glimcher L. H. Transcription of the interleukin 4 gene is regulated by multiple promoter elements. J Exp Med. 1993 Jun 1;177(6):1663–1674. doi: 10.1084/jem.177.6.1663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Tournier C., Whitmarsh A. J., Cavanagh J., Barrett T., Davis R. J. Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase. Proc Natl Acad Sci U S A. 1997 Jul 8;94(14):7337–7342. doi: 10.1073/pnas.94.14.7337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Tugores A., Alonso M. A., Sánchez-Madrid F., de Landázuri M. O. Human T cell activation through the activation-inducer molecule/CD69 enhances the activity of transcription factor AP-1. J Immunol. 1992 Apr 1;148(7):2300–2306. [PubMed] [Google Scholar]
  47. Wenner C. A., Szabo S. J., Murphy K. M. Identification of IL-4 promoter elements conferring Th2-restricted expression during T helper cell subset development. J Immunol. 1997 Jan 15;158(2):765–773. [PubMed] [Google Scholar]
  48. Whitmarsh A. J., Davis R. J. Transcription factor AP-1 regulation by mitogen-activated protein kinase signal transduction pathways. J Mol Med (Berl) 1996 Oct;74(10):589–607. doi: 10.1007/s001090050063. [DOI] [PubMed] [Google Scholar]
  49. Zheng W., Flavell R. A. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997 May 16;89(4):587–596. doi: 10.1016/s0092-8674(00)80240-8. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES