The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4.
The molecular basis for the distinctive cytokine expression of CD4+ T helper 1 (Th1) and T helper 2 (Th2) subsets remains elusive. Here, we report that the proto-oncogene c-maf, a basic region/leucine zipper transcription factor, controls tissue-specific expression of IL-4. c-Maf is expressed in Th2 but not Th1 clones and is induced during normal precursor cell differentiation along a Th2 but not Th1 lineage. c-Maf binds to a c-Maf response element (MARE) in the proximal IL-4 promoter adjacent to a site footprinted by extracts from Th2 but not Th1 clones. Ectopic expression of c-Maf transactivates the IL-4 promoter in Th1 cells, B cells, and nonlymphoid cells, a function that maps to the MARE and Th2-specific footprint. Furthermore, c-Maf acts in synergy with the nuclear factor of activated T cells (NF-ATp) to initiate endogeneous IL-4 production by B cells. Manipulation of c-Maf may alter Th subset ratios in human disease.
Ho
I C
IC
Department of Cancer Biology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Hodge
M R
MR
Rooney
J W
JW
Glimcher
L H
LH
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D001483:Base Sequence; D015152:Blotting, Northern; D017252:CD3 Complex / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured / Q000502:physiology; D002874:Chromosome Mapping; D002999:Clone Cells / Q000502:physiology; D016207:Cytokines / Q000235:genetics; D018983:DNA Footprinting; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation / Q000502:physiology; D015723:Gene Library; D005816:Genetic Complementation Test; D015847:Interleukin-4 / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051257:Proto-Oncogene Proteins c-maf; D011994:Recombinant Proteins / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D012680:Sensitivity and Specificity; D013154:Spleen / Q000166:cytology; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics
D017252:CD3 Complex; D016207:Cytokines; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C495608:Maf protein, mouse; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051257:Proto-Oncogene Proteins c-maf; D011994:Recombinant Proteins; D012097:Repressor Proteins; D015847:Interleukin-4