Abstract
The dual-specificity mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) inactivates MAP kinases by dephosphorylation. Here we show that the proinflammatory cytokine interleukin (IL)-17A induces adult mouse primary cardiac fibroblast (CF) proliferation and migration via IL-17 receptor A//IL-17 receptor C-dependent MKP-1 suppression, and activation of p38 MAPK and ERK1/2. IL-17A mediated p38 MAPK and ERK1/2 activation is inhibited by MKP-1 overexpression, but prolonged by MKP-1 knockdown. IL-17A induced miR-101 expression via PI3K/Akt, and miR-101 inhibitor reversed MKP-1 down regulation. Importantly, MKP-1 knockdown, pharmacological inhibition of p38 MAPK and ERK1/2, or overexpression of dominant negative MEK1, each markedly attenuated IL-17A-mediated CF proliferation and migration. Similarly, IL-17F and IL-17A/F heterodimer that also signal via IL-17RA/IL-17RC, stimulated CF proliferation and migration. These results indicate that IL-17A stimulates CF proliferation and migration via Akt/miR-101/MKP-1-dependent p38 MAPK and ERK1/2 activation. These studies support a potential role for IL-17 in cardiac fibrosis and adverse myocardial remodeling.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Cell Movement / drug effects
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Cell Movement / genetics*
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Cell Proliferation / drug effects
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Dual Specificity Phosphatase 1 / antagonists & inhibitors
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Dual Specificity Phosphatase 1 / deficiency
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Dual Specificity Phosphatase 1 / genetics*
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Fibrosis / genetics
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Fibrosis / metabolism*
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Fibrosis / pathology
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Gene Expression
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Genetic Vectors / genetics
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Genetic Vectors / metabolism
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Interleukin-17 / genetics
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Interleukin-17 / metabolism*
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Mice
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Myocardium / metabolism*
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Myocardium / pathology
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, Interleukin-17 / genetics
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Receptors, Interleukin-17 / metabolism
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Signal Transduction* / drug effects
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Transcription, Genetic
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Transfection
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Ventricular Remodeling
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Enzyme Inhibitors
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Interleukin-17
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MicroRNAs
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Receptors, Interleukin-17
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases
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Dual Specificity Phosphatase 1
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Dusp1 protein, mouse