Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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B-Lymphocytes / physiology
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Base Sequence
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Blotting, Northern
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CD3 Complex / genetics
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Cell Differentiation / genetics
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Cells, Cultured / physiology
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Chromosome Mapping
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Clone Cells / physiology
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Cytokines / genetics
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DNA Footprinting
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DNA, Complementary / genetics
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DNA-Binding Proteins / genetics*
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Gene Expression Regulation / physiology
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Gene Library
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Genetic Complementation Test
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Interleukin-4 / genetics*
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Lymphoma / genetics
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Mice
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Mice, Inbred BALB C
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Molecular Sequence Data
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Promoter Regions, Genetic / genetics
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Proto-Oncogene Mas
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins c-maf
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Recombinant Proteins / genetics
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Repressor Proteins / genetics
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Sensitivity and Specificity
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Spleen / cytology
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T-Lymphocytes, Helper-Inducer / physiology
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Transcription, Genetic / genetics
Substances
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CD3 Complex
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Cytokines
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DNA, Complementary
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DNA-Binding Proteins
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MAS1 protein, human
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Maf protein, mouse
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-maf
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Recombinant Proteins
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Repressor Proteins
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Interleukin-4