Negative regulation of interleukin 2 transcription by the glucocorticoid receptor

doi:10.1084/jem.175.5.1235

This Article

	Full Text (PDF, 1498K)
	Alert me when this article is cited
	Citation Map

Services

	Email this article
	Similar articles in this journal
	Similar articles in PubMed
	Alert me to new content in the JEM
	Download to citation manager

Citing Articles

	Citing Articles via HighWire
	Citing Articles via CrossRef
	Citing Articles via Google Scholar

Google Scholar

	Articles by Northrop, J. P.
	Articles by Mattila, P. S.
	Search for Related Content

PubMed

	PubMed Citation
	Articles by Northrop, J. P.
	Articles by Mattila, P. S.


Social Bookmarking

	What's this?

ARTICLES

Negative regulation of interleukin 2 transcription by the glucocorticoid receptor

JP Northrop, GR Crabtree and PS Mattila
Department of Pathology, Stanford University School of Medicine, California 94305.

Glucocorticoid-dependent transcriptional enhancement is known to occur through the interaction of the glucocorticoid receptor (GR) with specific DNA response elements. In contrast, negative regulation of gene expression by this class of hormone is less well understood. Glucocorticoids are potent immunosuppressive agents acting primarily by inhibiting T lymphocyte activation and lymphokine production. Interleukin 2 (IL-2) gene expression, a critical early event during T lymphocyte activation, is inhibited in glucocorticoid-sensitive cells by hormone treatment. We have studied the mechanism of this inhibition. In transgenic mice carrying c-myc linked to the IL-2 enhancer, mitogen- induced expression of the transgene is inhibited by concurrent glucocorticoid treatment, while a similar transgene construct driven by three copies of the binding site for nuclear factor of activated T cells is not inhibited. Cotransfection experiments into glucocorticoid- insensitive jurkat cells show that the NH2 terminus of the glucocorticoid receptor is dispensable for inhibition of the IL-2 enhancer but that an intact DNA binding domain, although not necessarily binding to DNA, is required. Hybrid GRs containing the DNA binding domains of either the estrogen receptor (ER) or thyroid receptor, as well as the entire wild-type ER, all function as repressors of the IL-2 enhancer. We have localized the site of inhibition to two sequences located in the proximal half of the enhancer. These sequences bind a similar, if not identical, inducible nuclear factor that has biologic characteristics that distinguish it from AP-1. The mechanism of IL-2 inhibition likely involves direct interactions between the GR and this factor.
Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Facebook Add to Reddit Reddit Add to Technorati Technorati Twitter What's this?

This article has been cited by other articles:

Harr, M. W., Rong, Y., Bootman, M. D., Roderick, H. L., Distelhorst, C. W. (2009). Glucocorticoid-mediated Inhibition of Lck Modulates the Pattern of T Cell Receptor-induced Calcium Signals by Down-regulating Inositol 1,4,5-Trisphosphate Receptors. J. Biol. Chem. 284: 31860-31871 [Abstract] [Full Text]
Lambert, K. C., Curran, E. M., Judy, B. M., Milligan, G. N., Lubahn, D. B., Estes, D. M. (2005). Estrogen Receptor {alpha} (ER{alpha}) Deficiency in Macrophages Results in Increased Stimulation of CD4+ T Cells while 17{beta}-Estradiol Acts through ER{alpha} to Increase IL-4 and GATA-3 Expression in CD4+ T Cells Independent of Antigen Presentation. J. Immunol. 175: 5716-5723 [Abstract] [Full Text]
Smit, P., Russcher, H., de Jong, F. H., Brinkmann, A. O., Lamberts, S. W. J., Koper, J. W. (2005). Differential Regulation of Synthetic Glucocorticoids on Gene Expression Levels of Glucocorticoid-Induced Leucine Zipper and Interleukin-2. J. Clin. Endocrinol. Metab. 90: 2994-3000 [Abstract] [Full Text]
Patel, F. A., Funder, J. W., Challis, J. R. G. (2003). Mechanism of Cortisol/Progesterone Antagonism in the Regulation of 15-Hydroxyprostaglandin Dehydrogenase Activity and Messenger Ribonucleic Acid Levels in Human Chorion and Placental Trophoblast Cells at Term. J. Clin. Endocrinol. Metab. 88: 2922-2933 [Abstract] [Full Text]
Almawi, W. Y., Melemedjian, O. K. (2002). Molecular mechanisms of glucocorticoid antiproliferative effects: antagonism of transcription factor activity by glucocorticoid receptor. J. Leukoc. Biol. 71: 9-15 [Abstract] [Full Text]
Trevillyan, J. M., Chiou, X. G., Chen, Y.-W., Ballaron, S. J., Sheets, M. P., Smith, M. L., Wiedeman, P. E., Warrior, U., Wilkins, J., Gubbins, E. J., Gagne, G. D., Fagerland, J., Carter, G. W., Luly, J. R., Mollison, K. W., Djuric, S. W. (2001). Potent Inhibition of NFAT Activation and T Cell Cytokine Production by Novel Low Molecular Weight Pyrazole Compounds. J. Biol. Chem. 276: 48118-48126 [Abstract] [Full Text]
Newton, R. (2000). Molecular mechanisms of glucocorticoid action: what is important?. Thorax 55: 603-613 [Full Text]
Chen, R., Burke, T. F., Cumberland, J. E., Brummet, M., Beck, L. A., Casolaro, V., Georas, S. N. (2000). Glucocorticoids Inhibit Calcium- and Calcineurin-Dependent Activation of the Human IL-4 Promoter. J. Immunol. 164: 825-832 [Abstract] [Full Text]
Bamberger, C. M., Else, T., Bamberger, A.-M., Ulrich Beil, F., Schulte, H. M. (1999). Dissociative Glucocorticoid Activity of Medroxyprogesterone Acetate in Normal Human Lymphocytes. J. Clin. Endocrinol. Metab. 84: 4055-4061 [Abstract] [Full Text]
Perez-Melgosa, M., Hollenbaugh, D., Wilson, C. B. (1999). Cutting Edge: CD40 Ligand Is a Limiting Factor in the Humoral Response to T Cell-Dependent Antigens. J. Immunol. 163: 1123-1127 [Abstract] [Full Text]
Wargnier, A., Lafaurie, C., Legros-Maida, S., Bourge, J.-F., Sigaux, F., Sasportes, M., Paul, P. (1998). Down-regulation of Human Granzyme B Expression by Glucocorticoids. DEXAMETHASONE INHIBITS BINDING TO THE Ikaros AND AP-1 REGULATORY ELEMENTS OF THE GRANZYME B PROMOTER. J. Biol. Chem. 273: 35326-35331 [Abstract] [Full Text]
Ballester, A., Velasco, A., Tobena, R., Alemany, S. (1998). Cot Kinase Activates Tumor Necrosis Factor-alpha Gene Expression in a Cyclosporin A-resistant Manner. J. Biol. Chem. 273: 14099-14106 [Abstract] [Full Text]
Mori, A., Kaminuma, O., Suko, M., Inoue, S., Ohmura, T., Hoshino, A., Asakura, Y., Miyazawa, K., Yokota, T., Okumura, Y., Ito, K., Okudaira, H. (1997). Two Distinct Pathways of Interleukin-5 Synthesis in Allergen-Specific Human T-Cell Clones Are Suppressed by Glucocorticoids. Blood 89: 2891-2900 [Abstract] [Full Text]
Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A., Karin, M. (1995). Immunosuppression by Glucocorticoids: Inhibition of NF-kappaB Activity Through Induction of IkappaB Sy nthesis. Science 270: 286-290 [Abstract]
Cippitelli, M., Sica, A., Viggiano, V., Ye, J., Ghosh, P., Birrer, M. J., Young, H. A. (1995). Negative Transcriptional Regulation of the Interferon-[IMAGE] Promoter by Glucocorticoids and Dominant Negative Mutants of c-Jun. J. Biol. Chem. 270: 12548-12556 [Abstract] [Full Text]
Barke, R. A., Roy, S., Chapin, R. B., Charboneau, R. (1994). The Role of Programmed Cell Death (Apoptosis) in Thymic Involution Following Sepsis. Arch Surg 129: 1256-1262 [Abstract]
Ullman, K S, Northrop, J P, Admon, A, Crabtree, G R (1993). Jun family members are controlled by a calcium-regulated, cyclosporin A-sensitive signaling pathway in activated T lymphocytes.. Genes Dev. 7: 188-196 [Abstract]
Mittelstadt, P. R., Ashwell, J. D. (2001). Inhibition of AP-1 by the Glucocorticoid-inducible Protein GILZ. J. Biol. Chem. 276: 29603-29610 [Abstract] [Full Text]