Skip to main content

Some NLM-NCBI services and products are experiencing heavy traffic, which may affect performance and availability. We apologize for the inconvenience and appreciate your patience. For assistance, please contact our Help Desk at info@ncbi.nlm.nih.gov.

Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Dec 1;89(23):11518–11522. doi: 10.1073/pnas.89.23.11518

Tumor necrosis factor alpha response elements in the HLA-DRA promoter: identification of a tumor necrosis factor alpha-induced DNA-protein complex in astrocytes.

R B Panek 1, H Moses 1, J P Ting 1, E N Benveniste 1
PMCID: PMC50583  PMID: 1454841

Abstract

The cytokine tumor necrosis factor alpha (TNF-alpha) alone does not induce class II major histocompatibility complex (MHC) expression in most primary cells but can regulate ongoing class II expression in either a positive or negative fashion. The mechanism(s) by which TNF-alpha enhances interferon gamma (IFN-gamma)-induced class II expression was examined in a primary cell type, the astrocyte, by transient transfection of the HLA-DRA promoter linked to a chloramphenicol acetyltransferase reporter gene (DRA-CAT). We show that TNF-alpha, while having no effect on its own, can synergize with IFN-gamma to increase the level of promoter activity of a DRA-CAT construct. Three known sequences--W, X, and Y--are required for TNF-alpha enhancement of IFN-gamma-induced promoter activity. The corollary effect of TNF-alpha on DNA-binding proteins specific for these elements was examined. A previous report described a DNA-binding protein, IFN-gamma-enhanced factor X (IFNEX), which is upregulated by IFN-gamma in astrocytes and is specific for the X box of the DRA promoter. In this study, we found that TNF-alpha alone did not induce any nuclear proteins; however, combined treatment of astrocytes with both IFN-gamma and TNF-alpha induced a DNA-protein complex of slower electrophoretic mobility than IFNEX. The TNF-alpha-induced complex (TIC-X) has specificity for the X element of the DRA promoter. These results suggest a mechanism by which TNF-alpha enhances IFN-gamma-induced class II MHC expression via the formation of TIC-X.

Full text

PDF
11518

Images in this article

Selected References

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

  1. Arenzana-Seisdedos F., Mogensen S. C., Vuillier F., Fiers W., Virelizier J. L. Autocrine secretion of tumor necrosis factor under the influence of interferon-gamma amplifies HLA-DR gene induction in human monocytes. Proc Natl Acad Sci U S A. 1988 Aug;85(16):6087–6091. doi: 10.1073/pnas.85.16.6087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Basham T. Y., Merigan T. C. Recombinant interferon-gamma increases HLA-DR synthesis and expression. J Immunol. 1983 Apr;130(4):1492–1494. [PubMed] [Google Scholar]
  3. Benacerraf B. Role of MHC gene products in immune regulation. Science. 1981 Jun 12;212(4500):1229–1238. doi: 10.1126/science.6165083. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Benveniste E. N. Cytokines: influence on glial cell gene expression and function. Chem Immunol. 1992;52:106–153. [PubMed] [Google Scholar]
  6. Benveniste E. N., Sparacio S. M., Bethea J. R. Tumor necrosis factor-alpha enhances interferon-gamma-mediated class II antigen expression on astrocytes. J Neuroimmunol. 1989 Dec;25(2-3):209–219. doi: 10.1016/0165-5728(89)90139-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bignami A., Eng L. F., Dahl D., Uyeda C. T. Localization of the glial fibrillary acidic protein in astrocytes by immunofluorescence. Brain Res. 1972 Aug 25;43(2):429–435. doi: 10.1016/0006-8993(72)90398-8. [DOI] [PubMed] [Google Scholar]
  8. Brenner D. A., O'Hara M., Angel P., Chojkier M., Karin M. Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha. Nature. 1989 Feb 16;337(6208):661–663. doi: 10.1038/337661a0. [DOI] [PubMed] [Google Scholar]
  9. Chung I. Y., Benveniste E. N. Tumor necrosis factor-alpha production by astrocytes. Induction by lipopolysaccharide, IFN-gamma, and IL-1 beta. J Immunol. 1990 Apr 15;144(8):2999–3007. [PubMed] [Google Scholar]
  10. Cogswell J. P., Basta P. V., Ting J. P. X-box-binding proteins positively and negatively regulate transcription of the HLA-DRA gene through interaction with discrete upstream W and V elements. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7703–7707. doi: 10.1073/pnas.87.19.7703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cogswell J. P., Zeleznik-Le N., Ting J. P. Transcriptional regulation of the HLA-DRA gene. Crit Rev Immunol. 1991;11(2):87–112. [PubMed] [Google Scholar]
  12. Fierz W., Endler B., Reske K., Wekerle H., Fontana A. Astrocytes as antigen-presenting cells. I. Induction of Ia antigen expression on astrocytes by T cells via immune interferon and its effect on antigen presentation. J Immunol. 1985 Jun;134(6):3785–3793. [PubMed] [Google Scholar]
  13. 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]
  14. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Markmann J., Lo D., Naji A., Palmiter R. D., Brinster R. L., Heber-Katz E. Antigen presenting function of class II MHC expressing pancreatic beta cells. Nature. 1988 Dec 1;336(6198):476–479. doi: 10.1038/336476a0. [DOI] [PubMed] [Google Scholar]
  17. Massa P. T., ter Meulen V., Fontana A. Hyperinducibility of Ia antigen on astrocytes correlates with strain-specific susceptibility to experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4219–4223. doi: 10.1073/pnas.84.12.4219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Moses H., Panek R. B., Benveniste E. N., Ting J. P. Usage of primary cells to delineate IFN-gamma-responsive DNA elements in the HLA-DRA promoter and to identify a novel IFN-gamma-enhanced nuclear factor. J Immunol. 1992 Jun 1;148(11):3643–3651. [PubMed] [Google Scholar]
  19. Moses H., Sasaki A., Ting J. P. Identification of an interferon-gamma-responsive element of a class II major histocompatibility gene in rat type 1 astrocytes. J Neuroimmunol. 1991 Mar;31(3):273–278. doi: 10.1016/0165-5728(91)90049-d. [DOI] [PubMed] [Google Scholar]
  20. Ono S. J., Liou H. C., Davidon R., Strominger J. L., Glimcher L. H. Human X-box-binding protein 1 is required for the transcription of a subset of human class II major histocompatibility genes and forms a heterodimer with c-fos. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4309–4312. doi: 10.1073/pnas.88.10.4309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pober J. S., Gimbrone M. A., Jr, Cotran R. S., Reiss C. S., Burakoff S. J., Fiers W., Ault K. A. Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon. J Exp Med. 1983 Apr 1;157(4):1339–1353. doi: 10.1084/jem.157.4.1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Reith W., Barras E., Satola S., Kobr M., Reinhart D., Sanchez C. H., Mach B. Cloning of the major histocompatibility complex class II promoter binding protein affected in a hereditary defect in class II gene regulation. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4200–4204. doi: 10.1073/pnas.86.11.4200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Seed B., Sheen J. Y. A simple phase-extraction assay for chloramphenicol acyltransferase activity. Gene. 1988 Jul 30;67(2):271–277. doi: 10.1016/0378-1119(88)90403-9. [DOI] [PubMed] [Google Scholar]
  24. Servenius B., Rask L., Peterson P. A. Class II genes of the human major histocompatibility complex. The DO beta gene is a divergent member of the class II beta gene family. J Biol Chem. 1987 Jun 25;262(18):8759–8766. [PubMed] [Google Scholar]
  25. Sparacio S. M., Zhang Y., Vilcek J., Benveniste E. N. Cytokine regulation of interleukin-6 gene expression in astrocytes involves activation of an NF-kappa B-like nuclear protein. J Neuroimmunol. 1992 Aug;39(3):231–242. doi: 10.1016/0165-5728(92)90257-l. [DOI] [PubMed] [Google Scholar]
  26. Vidovic M., Sparacio S. M., Elovitz M., Benveniste E. N. Induction and regulation of class II major histocompatibility complex mRNA expression in astrocytes by interferon-gamma and tumor necrosis factor-alpha. J Neuroimmunol. 1990 Dec;30(2-3):189–200. doi: 10.1016/0165-5728(90)90103-T. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Watanabe Y., Jacob C. O. Regulation of MHC class II antigen expression. Opposing effects of tumor necrosis factor-alpha on IFN-gamma-induced HLA-DR and Ia expression depends on the maturation and differentiation stage of the cell. J Immunol. 1991 Feb 1;146(3):899–905. [PubMed] [Google Scholar]
  28. Zeleznik-Le N. J., Azizkhan J. C., Ting J. P. Affinity-purified CCAAT-box-binding protein (YEBP) functionally regulates expression of a human class II major histocompatibility complex gene and the herpes simplex virus thymidine kinase gene. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1873–1877. doi: 10.1073/pnas.88.5.1873. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES