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Regulation of Th2 Cytokine Genes by p38 MAPK-Mediated Phosphorylation of GATA-3¹

Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, United Kingdom

GATA-3 plays a critical role in allergic diseases by regulating the release of cytokines from Th2 lymphocytes. However, the molecular mechanisms involved in the regulation of GATA-3 in human T lymphocytes are not yet understood. Using small interfering RNA to knock down GATA-3, we have demonstrated its critical role in regulating IL-4, IL-5, and IL-13 release from a human T cell line. Specific stimulation of T lymphocytes by costimulation of CD3 and CD28 to mimic activation by APCs induces translocation of GATA-3 from the cytoplasm to the nucleus, with binding to the promoter region of Th2 cytokine genes, as determined by chromatin immunoprecipitation. GATA-3 nuclear translocation is dependent on its phosphorylation on serine residues by p38 MAPK, which facilitates interaction with the nuclear transporter protein importin-. This provides a means whereby allergen exposure leads to the expression of Th2 cytokines, and this novel mechanism may provide new approaches to treating allergic diseases.

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.

¹ This study was supported by an unrestricted research grant from GlaxoSmithKline. K.M. was funded by the Thai government, and E.J. was supported by the Asmarley Trust.

² Current address: Division of Respiratory Disease and Tuberculosis, Department of Internal Medicine, Faculty of Medicine, Mahidol University, Siriraj Hospital, Bangkok 10700, Thailand.

³ Address correspondence and reprint requests to Dr. Peter J. Barnes, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, U.K. E-mail address: p.j.barnes{at}imperial.ac.uk

⁴ Abbreviations used in this paper: NLS, nuclear localization sequence; ATF, activated transcription factor; ChIP, chromatin immunoprecipitation; CIP, calf intestinal phosphatase; DAPI, 4',6'-diamidino-2-phenylindole; NaPi, sodium pyrophosphate; siRNA, small interfering RNA.

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