title: Dual-Specificity Phosphatase 1 and Tristetraprolin Cooperate To Regulate Macrophage Responses to Lipopolysaccharide.
abstract: Dual-specificity phosphatase (DUSP) 1 dephosphorylates and inactivates members of the MAPK superfamily, in particular, JNKs, p38α, and p38β MAPKs. It functions as an essential negative regulator of innate immune responses, hence disruption of the Dusp1 gene renders mice extremely sensitive to a wide variety of experimental inflammatory challenges. The principal mechanisms behind the overexpression of inflammatory mediators by Dusp1(-/-) cells are not known. In this study, we use a genetic approach to identify an important mechanism of action of DUSP1, involving the modulation of the activity of the mRNA-destabilizing protein tristetraprolin. This mechanism is key to the control of essential early mediators of inflammation, TNF, CXCL1, and CXCL2, as well as the anti-inflammatory cytokine IL-10. The same mechanism also contributes to the regulation of a large number of transcripts induced by treatment of macrophages with LPS. These findings demonstrate that modulation of the phosphorylation status of tristetraprolin is an important physiological mechanism by which innate immune responses can be controlled.
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Tim
authors.initials: T
authors.lastname: Smallie
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Ewan A
authors.initials: EA
authors.lastname: Ross
authors.affiliation: Faculty of Pharmacy, The University of Sydney, New South Wales 2006, Australia; and.
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Helen E
authors.initials: HE
authors.lastname: Cunliffe
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Tina
authors.initials: T
authors.lastname: Tang
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Dalya R
authors.initials: DR
authors.lastname: Rosner
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Michael L
authors.initials: ML
authors.lastname: Ridley
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Saklatvala
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, United Kingdom.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Dean
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom; a.r.clark@bham.ac.uk.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Clark
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D054426:Chemokine CXCL2 / Q000235:genetics / Q000276:immunology; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D048290:Mitogen-Activated Protein Kinase 11 / Q000235:genetics / Q000276:immunology; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D061251:Primary Cell Culture; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D051816:Tristetraprolin / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; C497553:Zfp36 protein, mouse; D016753:Interleukin-10; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14; D048670:MAP Kinase Kinase 4; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse