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

J. Biol. Chem., Vol. 280, Issue 31, 28177-28185, August 5, 2005

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/31/28177    most recent M502038200v1 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 Tykocinski, L.-O. Articles by Radbruch, A. Search for Related Content PubMed PubMed Citation Articles by Tykocinski, L.-O. Articles by Radbruch, A.

A Critical Control Element for Interleukin-4 Memory Expression in T Helper Lymphocytes^*

From the ^aDeutsches Rheuma-Forschungszentrum, Berlin 10117, Germany, ^bWellcome Trust CR UK Institute, Cambridge CB2 1QR, United Kingdom, ^cInstitute of Experimental Immunology, University Hospital Zürich, Zürich 8091, Switzerland, ^eLaboratory of Immunology, National Institutes of Health, Bethesda, Maryland 20892, ^gMax Delbrück Center for Molecular Medicine, Berlin 13122, Germany, ^hUniversity Hospital Charité, Humboldt University, Berlin 10117, Germany, ⁱUniversität des Saarlandes, Saarbrücken 66041, Germany

Naive T helper (Th) lymphocytes are induced to express the il4 (interleukin-4) gene by simultaneous signaling through the T cell receptor and the interleukin (IL)-4 receptor. Upon restimulation with antigen, such preactivated Th lymphocytes can reexpress the il4 gene independent of IL-4 receptor signaling. This memory for expression of the il4 gene depends on epigenetic modification of the il4 gene locus and an increased expression of GATA-3, the key transcription factor for Th2 differentiation. Here, we have identified a phylogenetically conserved sequence, the conserved intronic regulatory element, in the first intron of the il4 gene containing a tandem GATA-3 binding site. We show that GATA-3 binds to this sequence in a position- and orientation-dependent manner, in vitro and in vivo. DNA demethylation and histone acetylation of this region occurs early and selectively in differentiating, IL-4-secreting Th2 lymphocytes. Deletion of the conserved element by replacement of the first exon and part of the first intron of the il4 gene with gfp leads to a defect in the establishment of memory for expression of IL-4, in that reexpression of IL-4 still requires costimulation by exogenous IL-4. The conserved intronic regulatory element thus links the initial epigenetic modification of the il4 gene to GATA-3 and serves as a genetic control element for memory expression of IL-4.

Received for publication, February 23, 2005 , and in revised form, May 18, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants SFB 421 and SFB 618. 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.

The on-line version of this article (available at http://www.jbc.org) contains an additional figure.

^d A fellow of the Ernst Schering Research Foundation.

^f Supported by the Boehringer Ingelheim Fonds Ph.D. fellowship.

^j To whom correspondence should be addressed: Deutsches Rheumaforschungszentrum Berlin, Schumannstrasse 21/22, 10117 Berlin, Germany. Tel.: 49-30-28460-600; Fax: 49-30-28460603; E-mail: radbruch{at}drfz.de.

This article has been cited by other articles:

				C. de Lalla, N. Festuccia, I. Albrecht, H.-D. Chang, G. Andolfi, U. Benninghoff, F. Bombelli, G. Borsellino, A. Aiuti, A. Radbruch, et al. Innate-Like Effector Differentiation of Human Invariant NKT Cells Driven by IL-7 J. Immunol., April 1, 2008; 180(7): 4415 - 4424. [Abstract] [Full Text] [PDF]

				R. L. Miller and S.-m. Ho Environmental Epigenetics and Asthma: Current Concepts and Call for Studies Am. J. Respir. Crit. Care Med., March 15, 2008; 177(6): 567 - 573. [Abstract] [Full Text] [PDF]

				J. Liu, M. Ballaney, U. Al-alem, C. Quan, X. Jin, F. Perera, L.-C. Chen, and R. L. Miller Combined Inhaled Diesel Exhaust Particles and Allergen Exposure Alter Methylation of T Helper Genes and IgE Production In Vivo Toxicol. Sci., March 1, 2008; 102(1): 76 - 81. [Abstract] [Full Text] [PDF]

				S. T. Kim, P. E. Fields, and R. A. Flavell Demethylation of a specific hypersensitive site in the Th2 locus control region PNAS, October 23, 2007; 104(43): 17052 - 17057. [Abstract] [Full Text] [PDF]

				S. Rose, M. Lichtenheld, M. R. Foote, and B. Adkins Murine Neonatal CD4+ Cells Are Poised for Rapid Th2 Effector-Like Function J. Immunol., March 1, 2007; 178(5): 2667 - 2678. [Abstract] [Full Text] [PDF]