Regulation of IL-4 expression by the transcription factor JunB during T helper cell differentiation.
The molecular basis for restricted cytokine expression by T helper 1 (Th1) and T helper 2 (Th2) cells is unclear. Previous studies found that P1, an element of the interleukin 4 (IL-4) promoter that binds AP-1, is important for Th2-restricted IL-4 expression. Here we show that JunB, but not the other Jun family members, was selectively induced in Th2 cells and not in Th1 cells during differentiation. JunB has previously been considered to be a negative regulator of transcription. However, we show that JunB binds directly to the P1 site and synergizes with c-Maf to activate an IL-4 luciferase reporter gene. JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation. In transgenic mice, elevated JunB levels caused increased expression of several Th2 cytokines in developing Th1 cells. JunB also upregulated IL-4 expression in response to immunization. Thus, the early increase of JunB protein in Th2 cells can provide the specificity for c-Maf in IL-4 expression during T cell development and directs thereby Th2 differentiation.
Li
B
B
Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, New Haven CT 06520, USA.
Tournier
C
C
Davis
R J
RJ
Flavell
R A
RA
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D051257:Proto-Oncogene Proteins c-maf; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation
D016207:Cytokines; D004268:DNA-Binding Proteins; C495607:MAF protein, human; C495608:Maf protein, mouse; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D051257:Proto-Oncogene Proteins c-maf; D015847:Interleukin-4; D004247:DNA; D017871:Calcium-Calmodulin-Dependent Protein Kinases