Abstract
Natural helper (NH) cells, a member of Lin(-)IL-2R(+)IL-7R(+)IL-25R(+)IL-33R(+)GATA3(+) group 2 innate lymphoid cell subset, are characterized by the expression of transcription factors GATA3 and RORα and production of large amounts of Th2 cytokines such as IL-5, IL-6, and IL-13 upon IL-33 stimulation or a combination of IL-2 and IL-25. We have studied the signal transduction pathways critical for the cytokine expression and development of NH cell. Either stimulation with IL-33 or a combination of IL-2 and IL-25 induced p38 activation and phosphorylation of GATA3 in NH cells, and the phosphorylated form of GATA3 bound to the IL-5 and IL-13 promoters. All these events were blocked by SB203580, a p38 inhibitor. Inhibition of p38 also blocked IL-6 production. The mature NH cells lacking Gata3 were impaired in the proliferation and production of IL-5 and IL-13, but not IL-6, indicating that both p38 and GATA3 are critical for the proliferation and production of IL-5 and IL-13 and that the mechanisms downstream of p38 differ between IL-6 and IL-5/IL-13. In contrast, the NH cells lacking RORα showed no impairment in the proliferation and cytokine production, indicating that GATA3 but not RORα plays a pivotal role in the effector functions of mature NH cell. However, deletion of either GATA3 or RORα in hematopoietic stem cells severely blocked the development into NH cells. Our results demonstrate the important roles of p38 and GATA3 in NH cell functions.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic-Leucine Zipper Transcription Factors / deficiency
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Basic-Leucine Zipper Transcription Factors / physiology
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Cells, Cultured
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GATA3 Transcription Factor / immunology*
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GATA3 Transcription Factor / metabolism
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / immunology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Imidazoles / pharmacology
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Interleukins / biosynthesis
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Interleukins / genetics
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Interleukins / pharmacology
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Lymphopoiesis / drug effects
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Nuclear Receptor Subfamily 1, Group F, Member 1 / deficiency
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Nuclear Receptor Subfamily 1, Group F, Member 1 / physiology
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Phosphorylation / drug effects
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Promoter Regions, Genetic / drug effects
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Protein Processing, Post-Translational / drug effects
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Pyridines / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Specific Pathogen-Free Organisms
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T-Lymphocyte Subsets / enzymology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocytes, Helper-Inducer / enzymology
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T-Lymphocytes, Helper-Inducer / immunology*
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Transcription, Genetic / drug effects
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / immunology*
Substances
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Basic-Leucine Zipper Transcription Factors
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Imidazoles
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Interleukins
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Nfil3 protein, mouse
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Nuclear Receptor Subfamily 1, Group F, Member 1
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Pyridines
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Rora protein, mouse
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p38 Mitogen-Activated Protein Kinases
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SB 203580