HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 24, 23243-23250, June 17, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/24/23243    most recent M503659200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jee, Y.-K. Articles by Lavender, P. Search for Related Content PubMed PubMed Citation Articles by Jee, Y.-K. Articles by Lavender, P. Social Bookmarking                      What's this?

Repression of Interleukin-5 Transcription by the Glucocorticoid Receptor Targets GATA3 Signaling and Involves Histone Deacetylase Recruitment^*

Young-Koo Jee, Jane Gilmour, Audrey Kelly, Holly Bowen, David Richards, Cecilia Soh, Philip Smith¶, Catherine Hawrylowicz, David Cousins, Tak Lee, and Paul Lavender||

From the Department of Asthma, Allergy, and Respiratory Science, King's College London, 5th Floor, Thomas Guy House, Guy's Hospital, London SE1 9RT, United Kingdom, Division of Pulmonary Medicine and Allergy, College of Medicine, Dankook University, Cheonan 330-715, Republic of Korea, and ^¶Department of Endocrinology, St. Bartholomew's Hospital, London EC1A 7BE, United Kingdom

Glucocorticoids are the mainstay of asthma therapy and mediate the repression of a number of cytokine genes, such as Interleukin (IL)-4, -5, -13, and granulocyte macrophage colony-stimulating factor (GM-CSF), which are central to the pathogenesis of asthmatic airway inflammation. The glucocorticoid receptor (GR) mediates repression by a number of diverse mechanisms. We have previously suggested that one such repressive activity is by direct binding of GR to elements within the GM-CSF enhancer that are recognized by the nuclear factor of activated T cells·activator protein 1 (NF-AT·AP-1) complex. We reasoned that, because many cytokine genes activated in asthma are transcriptionally regulated by the recruitment of this complex to DNA, their binding sites might provide a target for GR to mediate its repressive effects. Here, we show that transcriptional repression of the Interleukin-5 gene involves recruitment of GR to a DNA region located within the IL-5 proximal promoter, which is bound by NF-AT and AP-1 proteins. GR recruitment had a profound effect upon the activation capacity of GATA3, which has a binding site close to the NF-AT·AP-1 domain in both IL-5 and IL-13 promoters. Repression by GR involves co-repressor recruitment, because treatment of transfected cells with the deacetylase inhibitor trichostatin A caused a partial relief of repression. Additionally, repression could be augmented by co-transfection of cells with a histone deacetylase (HDAC1). These data suggest that the local recruitment of GR causes repression by inhibiting transcriptional activation by GATA3, a key tissue-specific determinant of expression of Th2 cytokines.

Received for publication, April 4, 2005

^* This work was supported by Medical Research Council Programme Grant G9536930, Asthma UK Grant 02/53, the Charitable Foundation of Guy's and St. Thomas's, and GlaxoSmithKline. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Asthma, Allergy, and Respiratory Science, 5th Floor, Thomas Guy House, Guy's Hospital, London SE1 9RT, UK. Tel.: 44-207-188-0603; Fax: 44-207-403-8640; E-mail: paul.lavender{at}kcl.ac.uk.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				L. McKinley, J. F. Alcorn, A. Peterson, R. B. DuPont, S. Kapadia, A. Logar, A. Henry, C. G. Irvin, J. D. Piganelli, A. Ray, et al. TH17 Cells Mediate Steroid-Resistant Airway Inflammation and Airway Hyperresponsiveness in Mice J. Immunol., September 15, 2008; 181(6): 4089 - 4097. [Abstract] [Full Text] [PDF]

				J. N. Miner, B. Ardecky, K. Benbatoul, K. Griffiths, C. J. Larson, D. E. Mais, K. Marschke, J. Rosen, E. Vajda, L. Zhi, et al. Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein protein interaction profile PNAS, December 4, 2007; 104(49): 19244 - 19249. [Abstract] [Full Text] [PDF]

				U. De Fanis, F. Mori, R. J. Kurnat, W. K. Lee, M. Bova, N. F. Adkinson, and V. Casolaro GATA3 up-regulation associated with surface expression of CD294/CRTH2: a unique feature of human Th cells Blood, May 15, 2007; 109(10): 4343 - 4350. [Abstract] [Full Text] [PDF]