Abstract
We reported previously that c-kit ligation by membrane-bound stem cell factor (mSCF) boosts IL-6 production in dendritic cells (DCs) and a Th17-immune response. However, Th17 establishment also requires heterodimeric IL-23, but the mechanisms that regulate IL-23 gene expression in DCs are not fully understood. We show that IL-23p19 gene expression in lung DCs is dependent on mSCF, which is regulated by the metalloproteinase MMP-9. Th1-inducing conditions enhanced MMP-9 activity, causing cleavage of mSCF, whereas the opposite was true for Th17-promoting conditions. In MMP-9(-/-) mice, a Th1-inducing condition could maintain mSCF and enhance IL-23p19 in DCs, promoting IL-17-producing CD4(+) T cells in the lung. Conversely, mSCF cleavage from bone marrow DCs in vitro by rMMP-9 led to reduced IL-23p19 expression under Th17-inducing conditions, with dampening of intracellular AKT phosphorylation. Collectively, these results show that the c-kit/mSCF/MMP-9 axis regulates IL-23 gene expression in DCs to control IL-17 production in the lung.
Copyright © 2014 by The American Association of Immunologists, Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Membrane / genetics
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Dendritic Cells / cytology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Gene Expression Regulation / genetics
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Gene Expression Regulation / immunology*
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Interleukin-17 / genetics
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Interleukin-17 / immunology*
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Interleukin-17 / metabolism
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Interleukin-23 Subunit p19 / biosynthesis
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Interleukin-23 Subunit p19 / genetics
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Interleukin-23 Subunit p19 / immunology*
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Lung / cytology
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Lung / immunology*
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Lung / metabolism
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / immunology*
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Matrix Metalloproteinase 9 / metabolism
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Mice
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Mice, Knockout
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Phosphorylation / genetics
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Phosphorylation / immunology
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / immunology
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Proto-Oncogene Proteins c-akt / metabolism
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Stem Cell Factor / genetics
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Stem Cell Factor / immunology*
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Stem Cell Factor / metabolism
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Th1 Cells / cytology
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Th17 Cells / cytology
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Th17 Cells / immunology
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Th17 Cells / metabolism
Substances
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Il23a protein, mouse
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Interleukin-17
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Interleukin-23 Subunit p19
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Stem Cell Factor
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Proto-Oncogene Proteins c-akt
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Matrix Metalloproteinase 9
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Mmp9 protein, mouse