title: The MAPK-Activated Kinase MK2 Attenuates Dendritic Cell-Mediated Th1 Differentiation and Autoimmune Encephalomyelitis.
abstract: Dendritic cell (DC)-mediated inflammation induced via TLRs is promoted by MAPK-activated protein kinase (MK)-2, a substrate of p38 MAPK. In this study we show an opposing role of MK2, by which it consolidates immune regulatory functions in DCs through modulation of p38, ERK1/2-MAPK, and STAT3 signaling. During primary TLR/p38 signaling, MK2 mediates the inhibition of p38 activation and positively cross-regulates ERK1/2 activity, leading to a reduction of IL-12 and IL-1α/β secretion. Consequently, MK2 impairs secondary autocrine IL-1α signaling in DCs, which further decreases the IL-1α/p38 but increases the anti-inflammatory IL-10/STAT3 signaling route. Therefore, the blockade of MK2 activity enables human and murine DCs to strengthen proinflammatory effector mechanisms by promoting IL-1α-mediated Th1 effector functions in vitro. Furthermore, MK2-deficient DCs trigger Th1 differentiation and Ag-specific cytotoxicity in vivo. Finally, wild-type mice immunized with LPS in the presence of an MK2 inhibitor strongly accumulate Th1 cells in their lymph nodes. These observations correlate with a severe clinical course in DC-specific MK2 knockout mice compared with wild-type littermates upon induction of experimental autoimmune encephalitis. Our data suggest that MK2 exerts a profound anti-inflammatory effect that prevents DCs from prolonging excessive Th1 effector T cell functions and autoimmunity.
authors.affiliation: Department of Immunology, St. Anna Children's Cancer Research Institute, 1090 Vienna, Austria;
authors.forename: Klara
authors.initials: K
authors.lastname: Soukup
authors.affiliation: Department of Immunology, St. Anna Children's Cancer Research Institute, 1090 Vienna, Austria;
authors.forename: Angela
authors.initials: A
authors.lastname: Halfmann
authors.affiliation: Department of Immunology, St. Anna Children's Cancer Research Institute, 1090 Vienna, Austria;
authors.forename: Marie
authors.initials: M
authors.lastname: Le Bras
authors.affiliation: Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Emine
authors.initials: E
authors.lastname: Sahin
authors.affiliation: Department of Immunology, St. Anna Children's Cancer Research Institute, 1090 Vienna, Austria;
authors.forename: Sarah
authors.initials: S
authors.lastname: Vittori
authors.affiliation: Department of Immunology, St. Anna Children's Cancer Research Institute, 1090 Vienna, Austria;
authors.forename: Fiona
authors.initials: F
authors.lastname: Poyer
authors.affiliation: Department of Immunology, St. Anna Children's Cancer Research Institute, 1090 Vienna, Austria;
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schuh
authors.affiliation: Department of Immunology, St. Anna Children's Cancer Research Institute, 1090 Vienna, Austria;
authors.forename: Romana
authors.initials: R
authors.lastname: Luger
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Birgit
authors.initials: B
authors.lastname: Niederreiter
authors.affiliation: Department of Thoracic Surgery, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Thomas
authors.initials: T
authors.lastname: Haider
authors.affiliation: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria; Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria;
authors.forename: Dagmar
authors.initials: D
authors.lastname: Stoiber
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Stephan
authors.initials: S
authors.lastname: Blüml
authors.affiliation: Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria;
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, 30625 Hannover, Germany; and.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kotlyarov
authors.affiliation: Institute of Physiological Chemistry, Hannover Medical School, 30625 Hannover, Germany; and.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gaestel
authors.affiliation: Activartis Biotech GmbH, 1090 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Felzmann
authors.affiliation: Department of Immunology, St. Anna Children's Cancer Research Institute, 1090 Vienna, Austria; alexander.dohnal@ccri.at.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Dohnal
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007114:Immunization; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D016753:Interleukin-10; D018664:Interleukin-12; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D050796:STAT3 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C556062:IL10 protein, mouse; C494087:Stat3 protein, mouse