Abstract
Mitogen-activated protein kinase (MAPK) phosphatases are dual-specificity phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues within MAPKs. DUSP6 preferentially dephosphorylates extracellular signal-regulated kinases 1 and 2 (ERK1/2) rendering them inactive. Here, we study the role of DUSP6 in CD4(+) T-cell function, differentiation, and inflammatory profile in the colon. Upon T-cell receptor (TCR) stimulation, DUSP6 knockout (Dusp6(-/-)) CD4(+) T cells showed increased ERK1/2 activation, proliferation, T helper 1 differentiation, and interferon-γ production, as well as a marked decrease in survival, interleukin- 17A (IL-17A) secretion, and regulatory T-cell function. To analyze the role of DUSP6 in vivo, we employed the Il10(-/-) model of colitis and generated Il10(-/-)/Dusp6(-/-) double-knockout mice. Il10(-/-)/Dusp6(-/-) mice suffered from accelerated and exacerbated spontaneous colitis, which was prevented by ERK1/2 inhibition. ERK1/2 inhibition also augmented regulatory T-cell differentiation in vitro and in vivo in both C57Bl/6 and Dusp6(-/-) mice. In summary, DUSP6 regulates CD4(+) T-cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation. DUSP6 might therefore be a potential intervention target for limiting aberrant T-cell responses in T-cell-mediated diseases, such as inflammatory bowel disease.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzamides / pharmacology
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Cell Differentiation
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Cell Proliferation
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Colitis / genetics
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Colitis / immunology*
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Colitis / pathology
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Colon / immunology*
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Colon / pathology
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Diphenylamine / analogs & derivatives
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Diphenylamine / pharmacology
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Disease Models, Animal
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Dual Specificity Phosphatase 6 / deficiency
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Dual Specificity Phosphatase 6 / genetics
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Dual Specificity Phosphatase 6 / immunology*
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Gene Expression Regulation
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Immunity, Mucosal
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interleukin-10 / deficiency
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Interleukin-10 / genetics
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Interleukin-10 / immunology*
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Interleukin-17 / genetics
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Interleukin-17 / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / immunology
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / immunology
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
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Signal Transduction
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T-Lymphocytes, Regulatory / immunology*
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T-Lymphocytes, Regulatory / pathology
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Th1 Cells / immunology*
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Th1 Cells / pathology
Substances
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Benzamides
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IL10 protein, mouse
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Interleukin-17
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Receptors, Antigen, T-Cell
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Interleukin-10
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Interferon-gamma
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mirdametinib
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Diphenylamine
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Dual Specificity Phosphatase 6
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Dusp6 protein, mouse