A 3' enhancer in the IL-4 gene regulates cytokine production by Th2 cells and mast cells.
Differentiation of naive T cells into mature Th2 cells is associated with the appearance of a complex pattern of DNase I hypersensitive (DH) sites within the IL-4/IL-13 cytokine gene cluster. We show here that targeted deletion of an inducible DH site, V(A), and the adjacent conserved DH site V (CNS-2) selectively compromises IL-4 gene transcription by differentiated Th2 cells and mast cells. In mast cells, the deletion abrogates IL-4 mRNA induction, an effect mimicked by deletion of the transcription factor NFAT1 (NFATc2), which binds DH site V(A). In T cells, the deletion impairs a process of response maturation, defined by progressive increases in IL-4 levels as Th2 differentiation proceeds. These results identify an essential enhancer which regulates IL-4 gene expression in two important cell lineages in vivo.
Solymar
Deborah C
DC
The Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Agarwal
Suneet
S
Bassing
Craig H
CH
Alt
Frederick W
FW
Rao
Anjana
A
D024509:3' Flanking Region; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D003850:Deoxyribonuclease I / Q000737:chemistry; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D018793:Interleukin-13 / Q000096:biosynthesis / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics*; D007700:Kinetics; D008407:Mast Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005810:Multigene Family; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000096:biosynthesis; D017384:Sequence Deletion; D018418:Th2 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D018793:Interleukin-13; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D015847:Interleukin-4; D003850:Deoxyribonuclease I