Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1991 Dec 1;174(6):1583–1592. doi: 10.1084/jem.174.6.1583

Repression of class II major histocompatibility complex genes by cyclic AMP is mediated by conserved promoter elements

PMCID: PMC2119024  PMID: 1660527

Abstract

The induction of cell surface expression of class II major histocompatibility complex (MHC) antigens by interleukin (IL)-4 and interferon (IFN)-gamma is inhibited by elevation of intracellular cyclic (c)AMP, which is caused by immunomodulatory agents such as E series prostaglandins (PGEs). To investigate the mechanism of this downregulation, we have analyzed the consequences of elevating intracellular cAMP on cell surface expression, mRNA levels, and promoter activity of the murine A alpha and E beta class II MHC genes. Elevation of cAMP resulted in a coordinate repression of both basal and inducible A alpha and E beta expression. 151 and 192 base pairs of A alpha and E beta promoter sequence, respectively, were sufficient for conferring repression by cAMP on a reporter gene. A mutational analysis of the A alpha promoter revealed that cAMP downregulation is mediated by the conserved S and X1 DNA elements, which are also necessary for induction by cytokines. Downregulation by cAMP was not dependent on an intact X2 site, which is identical in sequence to the CRE element which mediates the positive regulation of several genes by cAMP. These results identify the DNA elements which mediate repression of class II MHC genes by cAMP and show that the same DNA sequences can mediate both positive and negative regulation of class II MHC expression.

Full Text

The Full Text of this article is available as a PDF (1.2 MB).

Selected References

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

  1. Andersen L. C., Beaty J. S., Nettles J. W., Seyfried C. E., Nepom G. T., Nepoom B. S. Allelic polymorphism in transcriptional regulatory regions of HLA-DQB genes. J Exp Med. 1991 Jan 1;173(1):181–192. doi: 10.1084/jem.173.1.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Benoist C., Mathis D. Regulation of major histocompatibility complex class-II genes: X, Y and other letters of the alphabet. Annu Rev Immunol. 1990;8:681–715. doi: 10.1146/annurev.iy.08.040190.003341. [DOI] [PubMed] [Google Scholar]
  3. Betz M., Fox B. S. Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines. J Immunol. 1991 Jan 1;146(1):108–113. [PubMed] [Google Scholar]
  4. Boothby M., Gravallese E., Liou H. C., Glimcher L. H. A DNA binding protein regulated by IL-4 and by differentiation in B cells. Science. 1988 Dec 16;242(4885):1559–1562. doi: 10.1126/science.3144043. [DOI] [PubMed] [Google Scholar]
  5. Burmester G. R., Jahn B., Rohwer P., Zacher J., Winchester R. J., Kalden J. R. Differential expression of Ia antigens by rheumatoid synovial lining cells. J Clin Invest. 1987 Sep;80(3):595–604. doi: 10.1172/JCI113111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Case J. P., Lafyatis R., Kumkumian G. K., Remmers E. F., Wilder R. L. IL-1 regulation of transin/stromelysin transcription in rheumatoid synovial fibroblasts appears to involve two antagonistic transduction pathways, an inhibitory, prostaglandin-dependent pathway mediated by cAMP, and a stimulatory, protein kinase C-dependent pathway. J Immunol. 1990 Dec 1;145(11):3755–3761. [PubMed] [Google Scholar]
  7. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  8. Dedrick R. L., Jones P. P. Sequence elements required for activity of a murine major histocompatibility complex class II promoter bind common and cell-type-specific nuclear factors. Mol Cell Biol. 1990 Feb;10(2):593–604. doi: 10.1128/mcb.10.2.593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Freund Y. R., Dedrick R. L., Jones P. P. cis-acting sequences required for class II gene regulation by interferon gamma and tumor necrosis factor alpha in a murine macrophage cell line. J Exp Med. 1990 Apr 1;171(4):1283–1299. doi: 10.1084/jem.171.4.1283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Germain R. N., Malissen B. Analysis of the expression and function of class-II major histocompatibility complex-encoded molecules by DNA-mediated gene transfer. Annu Rev Immunol. 1986;4:281–315. doi: 10.1146/annurev.iy.04.040186.001433. [DOI] [PubMed] [Google Scholar]
  11. Gonzalez G. A., Montminy M. R. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 1989 Nov 17;59(4):675–680. doi: 10.1016/0092-8674(89)90013-5. [DOI] [PubMed] [Google Scholar]
  12. Gravallese E. M., Boothby M. R., Smas C. M., Glimcher L. H. A lipopolysaccharide-induced DNA-binding protein for a class II gene in B cells is distinct from NF-kappa B. Mol Cell Biol. 1989 Aug;9(8):3184–3192. doi: 10.1128/mcb.9.8.3184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Haas J. G., Baeuerle P. A., Riethmüller G., Ziegler-Heitbrock H. W. Molecular mechanisms in down-regulation of tumor necrosis factor expression. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9563–9567. doi: 10.1073/pnas.87.24.9563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Imagawa M., Chiu R., Karin M. Transcription factor AP-2 mediates induction by two different signal-transduction pathways: protein kinase C and cAMP. Cell. 1987 Oct 23;51(2):251–260. doi: 10.1016/0092-8674(87)90152-8. [DOI] [PubMed] [Google Scholar]
  15. Ivashkiv L. B., Liou H. C., Kara C. J., Lamph W. W., Verma I. M., Glimcher L. H. mXBP/CRE-BP2 and c-Jun form a complex which binds to the cyclic AMP, but not to the 12-O-tetradecanoylphorbol-13-acetate, response element. Mol Cell Biol. 1990 Apr;10(4):1609–1621. doi: 10.1128/mcb.10.4.1609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kaestner K. H., Flores-Riveros J. R., McLenithan J. C., Janicot M., Lane M. D. Transcriptional repression of the mouse insulin-responsive glucose transporter (GLUT4) gene by cAMP. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1933–1937. doi: 10.1073/pnas.88.5.1933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kara C. J., Glimcher L. H. In vivo footprinting of MHC class II genes: bare promoters in the bare lymphocyte syndrome. Science. 1991 May 3;252(5006):709–712. doi: 10.1126/science.1902592. [DOI] [PubMed] [Google Scholar]
  18. Kelley V. E., Winkelstein A., Izui S., Dixon F. J. Prostaglandin E1 inhibits T-cell proliferation and renal disease in MRL/1 mice. Clin Immunol Immunopathol. 1981 Nov;21(2):190–203. doi: 10.1016/0090-1229(81)90208-7. [DOI] [PubMed] [Google Scholar]
  19. Kouskoff V., Mantovani R. M., Candéias S. M., Dorn A., Staub A., Lisowska-Grospierre B., Griscelli C., Benoist C. O., Mathis D. J. NF-X, a transcription factor implicated in MHC class II gene regulation. J Immunol. 1991 May 1;146(9):3197–3204. [PubMed] [Google Scholar]
  20. Liou H. C., Boothby M. R., Finn P. W., Davidon R., Nabavi N., Zeleznik-Le N. J., Ting J. P., Glimcher L. H. A new member of the leucine zipper class of proteins that binds to the HLA DR alpha promoter. Science. 1990 Mar 30;247(4950):1581–1584. doi: 10.1126/science.2321018. [DOI] [PubMed] [Google Scholar]
  21. Liou H. C., Polla B. S., Aragnol D., Leserman L. D., Griffith I. J., Glimcher L. H. A tissue-specific DNase I-hypersensitive site in a class II A alpha gene is under trans-regulatory control. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2738–2742. doi: 10.1073/pnas.85.8.2738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Makoul G. T., Robinson D. R., Bhalla A. K., Glimcher L. H. Prostaglandin E2 inhibits the activation of cloned T cell hybridomas. J Immunol. 1985 Apr;134(4):2645–2650. [PubMed] [Google Scholar]
  23. Nguyen H. T., Medford R. M., Nadal-Ginard B. Reversibility of muscle differentiation in the absence of commitment: analysis of a myogenic cell line temperature-sensitive for commitment. Cell. 1983 Aug;34(1):281–293. doi: 10.1016/0092-8674(83)90159-9. [DOI] [PubMed] [Google Scholar]
  24. Novak T. J., Rothenberg E. V. cAMP inhibits induction of interleukin 2 but not of interleukin 4 in T cells. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9353–9357. doi: 10.1073/pnas.87.23.9353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Polla B. S., Ohara J., Paul W. E., Nabavi N., Myer A., Liou H. C., Shen F. W., Gillis S., Bonventre J. V., Glimcher L. H. Differential induction of class II gene expression in murine pre-B-cell lines by B-cell stimulatory factor-1 and by antibodies to B-cell surface antigens. J Mol Cell Immunol. 1988;3(6):363–373. [PubMed] [Google Scholar]
  26. Reith W., Herrero-Sanchez C., Kobr M., Silacci P., Berte C., Barras E., Fey S., Mach B. MHC class II regulatory factor RFX has a novel DNA-binding domain and a functionally independent dimerization domain. Genes Dev. 1990 Sep;4(9):1528–1540. doi: 10.1101/gad.4.9.1528. [DOI] [PubMed] [Google Scholar]
  27. Saito H., Maki R. A., Clayton L. K., Tonegawa S. Complete primary structures of the E beta chain and gene of the mouse major histocompatibility complex. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5520–5524. doi: 10.1073/pnas.80.18.5520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sheng M., Thompson M. A., Greenberg M. E. CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science. 1991 Jun 7;252(5011):1427–1430. doi: 10.1126/science.1646483. [DOI] [PubMed] [Google Scholar]
  29. Snyder D. S., Beller D. I., Unanue E. R. Prostaglandins modulate macrophage Ia expression. Nature. 1982 Sep 9;299(5879):163–165. doi: 10.1038/299163a0. [DOI] [PubMed] [Google Scholar]
  30. Wuthrich R. P., Glimcher L. H., Yui M. A., Jevnikar A. M., Dumas S. E., Kelley V. E. MHC class II, antigen presentation and tumor necrosis factor in renal tubular epithelial cells. Kidney Int. 1990 Feb;37(2):783–792. doi: 10.1038/ki.1990.46. [DOI] [PubMed] [Google Scholar]
  31. Zimmer T., Jones P. P. Combined effects of tumor necrosis factor-alpha, prostaglandin E2, and corticosterone on induced Ia expression on murine macrophages. J Immunol. 1990 Aug 15;145(4):1167–1175. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES