title: Dual-specificity phosphatase 6 regulates CD4+ T-cell functions and restrains spontaneous colitis in IL-10-deficient mice.
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.
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bertin
authors.affiliation: Networked Biomedical Research Center for Hepatic and Digestive Disease (CIBERehd), Institute of Health Carlos III, Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Lozano-Ruiz
authors.affiliation: Networked Biomedical Research Center for Hepatic and Digestive Disease (CIBERehd), Institute of Health Carlos III, Madrid, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Bachiller
authors.affiliation: Networked Biomedical Research Center for Hepatic and Digestive Disease (CIBERehd), Institute of Health Carlos III, Madrid, Spain.
authors.forename: I
authors.initials: I
authors.lastname: García-Martínez
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Herdman
authors.affiliation: Networked Biomedical Research Center for Hepatic and Digestive Disease (CIBERehd), Institute of Health Carlos III, Madrid, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Zapater
authors.affiliation: Networked Biomedical Research Center for Hepatic and Digestive Disease (CIBERehd), Institute of Health Carlos III, Madrid, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Francés
authors.affiliation: Networked Biomedical Research Center for Hepatic and Digestive Disease (CIBERehd), Institute of Health Carlos III, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Such
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, USA.
authors.forename: E
authors.initials: E
authors.lastname: Raz
authors.affiliation: 1] Division of Rheumatology, Allergy and Immunology, University of California San Diego, La Jolla, California, USA [2] Networked Biomedical Research Center for Hepatic and Digestive Disease (CIBERehd), Institute of Health Carlos III, Madrid, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: González-Navajas
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002454:Cell Differentiation; D049109:Cell Proliferation; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D054642:Dual Specificity Phosphatase 6 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D018928:Immunity, Mucosal; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D001549:Benzamides; C556062:IL10 protein, mouse; D020381:Interleukin-17; D011948:Receptors, Antigen, T-Cell; D016753:Interleukin-10; D007371:Interferon-gamma; C506614:mirdametinib; D004159:Diphenylamine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse