Regulation of Th2 cytokine genes by p38 MAPK-mediated phosphorylation of GATA-3.
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-alpha. 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.
Maneechotesuwan
Kittipong
K
Section of Airway Disease, National Heart and Lung Institute, Imperial College, London, United Kingdom.
Xin
Yao
Y
Ito
Kazuhiro
K
Jazrawi
Elen
E
Lee
Kang-Yun
KY
Usmani
Omar S
OS
Barnes
Peter J
PJ
Adcock
Ian M
IM
D021581:Active Transport, Cell Nucleus / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000276:immunology / Q000494:pharmacology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D028901:alpha Karyopherins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D034741:RNA, Small Interfering; D028901:alpha Karyopherins; D048051:p38 Mitogen-Activated Protein Kinases