Bruton's tyrosine kinase-mediated interleukin-2 gene activation in mast cells. Dependence on the c-Jun N-terminal kinase activation pathway.
Cross-linking of the high affinity IgE receptor (FcepsilonRI) on mast cells induces secretion of cytokines, including interleukin (IL)-2, through transcriptional activation of cytokine genes. Previously, defects in the gene coding for Bruton's tyrosine kinase (Btk) were shown to result in defective cytokine production in mast cells, and thereby mice carrying btk mutations exhibited diminished anaphylactic reactions in response to IgE and antigen. In this study, we provide evidence that the transcription factors involved in the IL-2 gene expression in T cells are also required for maximal activation of the IL-2 gene in FcepsilonRI-stimulated mast cells. Among them, AP-1 (Jun/Fos) and NF-AT were identified as candidate transcription factors that are regulated by Btk. Consistent with our previous data indicating that Btk regulates stress-activated protein kinases, c-Jun N-terminal kinase (JNK), c-Jun and other JNK-regulatable transcription factors are activated by FcepsilonRI cross-linking in a Btk-dependent manner. Further, FcepsilonRI-induced IL-2 gene activation is dependent on c-Jun and a component, SEK1, of its upstream activation pathway. Collectively, these data demonstrate that Btk regulates the transcription of the IL-2 gene through the JNK-regulatable transcription factors in FcepsilonRI-stimulated mast cells.
Hata
D
D
Division of Allergy, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
Kitaura
J
J
Hartman
S E
SE
Kawakami
Y
Y
Yokota
T
T
Kawakami
T
T
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D007376:Interleukin-2 / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017455:Receptors, IgE / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D017455:Receptors, IgE; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases