title: The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages.
abstract: Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-κB and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun-deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the anti-inflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels.
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hannemann
authors.affiliation: Preclinical Imaging Platform Erlangen, Institute of Radiology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Jordan
authors.affiliation: Laboratory of Systems Tumor Immunology, Department of Dermatology, University Hospital Erlangen, 91054 Erlangen, Germany; and.
authors.forename: Sushmita
authors.initials: S
authors.lastname: Paul
authors.affiliation: Division of Biochemistry, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Stephen
authors.initials: S
authors.lastname: Reid
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Hanns-Wolf
authors.initials: HW
authors.lastname: Baenkler
authors.affiliation: Division of Biochemistry, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Sophia
authors.identifier: 0000-0002-9185-6255
authors.initials: S
authors.lastname: Sonnewald
authors.affiliation: Preclinical Imaging Platform Erlangen, Institute of Radiology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bäuerle
authors.affiliation: Laboratory of Systems Tumor Immunology, Department of Dermatology, University Hospital Erlangen, 91054 Erlangen, Germany; and.
authors.forename: Julio
authors.identifier: 0000-0002-3076-5122
authors.initials: J
authors.lastname: Vera
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Internal Medicine 3-Rheumatology and Immunology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany; aline.bozec@uk-erlangen.de.
authors.forename: Aline
authors.identifier: 0000-0001-8174-2118
authors.initials: A
authors.lastname: Bozec
mesh_terms: D000818:Animals; D001119:Arginase / Q000276:immunology / Q000378:metabolism*; D001168:Arthritis / Q000276:immunology*; D002478:Cells, Cultured; D016000:Cluster Analysis; D051546:Cyclooxygenase 2 / Q000276:immunology / Q000378:metabolism*; D005260:Female; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; C574619:ARG1 protein, human; D001119:Arginase