Abstract
Th2 and mast cells are participants in the asthmatic response to allergens, and both cell types produce the cytokines interleukin (IL)-4 and IL-13. IL-13 in particular is both necessary and sufficient for experimental models of asthma. The transcription factor NFAT plays a central role in cytokine transcriptional regulation in both cell types. Here, we analyze the molecular basis of IL13 gene transcription in Th2 and mast cells. We show that NFAT1 is the major NFAT protein involved in regulating IL13 transcription in mast cells. Although NFAT2 is correctly expressed and regulated in mast cells, it does not contribute to IL13 gene transcription as shown by analysis of cells lacking NFAT2 and cells expressing a constitutively active version of NFAT2. The difference between NFAT1 and NFAT2 appears to be due to a preferential synergistic interaction of NFAT1 with GATA proteins at the IL13 promoter. We suggest that mast cells lack a co-activator protein that stabilizes the binding of NFAT2 to the IL13 promoter by interacting either with NFAT2 itself or with a DNA-bound complex of NFAT2 and GATA proteins.
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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Blotting, Western
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Bone Marrow Cells / cytology
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Bone Marrow Cells / metabolism
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Cell Differentiation
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Chromatin / metabolism
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Cytokines / metabolism
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DNA / metabolism
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DNA-Binding Proteins / physiology*
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Embryo, Mammalian / cytology
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Enzyme-Linked Immunosorbent Assay
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Gene Expression Regulation*
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Genes, Reporter
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Humans
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Immunohistochemistry
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Interleukin-13 / biosynthesis*
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Interleukin-13 / genetics*
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Interleukin-13 / metabolism
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Jurkat Cells
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Mast Cells / metabolism*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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NFATC Transcription Factors
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Nuclear Proteins*
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Plasmids / metabolism
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Precipitin Tests
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Promoter Regions, Genetic
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Protein Binding
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Protein Isoforms
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Ribonucleases / metabolism
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Stem Cells / metabolism
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T-Lymphocytes / metabolism
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Th2 Cells
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Time Factors
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Transcription Factors / physiology*
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Transcription, Genetic*
Substances
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Chromatin
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Cytokines
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DNA-Binding Proteins
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Interleukin-13
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NFATC Transcription Factors
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NFATC1 protein, human
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NFATC2 protein, human
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Nfatc1 protein, mouse
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Nuclear Proteins
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Protein Isoforms
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Transcription Factors
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DNA
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Ribonucleases