title: Attenuated TLR4/MAPK signaling in monocytes from patients with CRMO results in impaired IL-10 expression.
abstract: Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder of unknown origin. We previously demonstrated that monocytes from CRMO patients fail to express the immune-modulatory cytokine interleukin-10 (IL-10) in a chromatin dependent manner. Here, we demonstrate that attenuated extracellular-signal regulated kinase (ERK)1 and 2 signaling in response to TLR4 activation results in failure to induce IL-10 expression in monocytes from CRMO patients. Attenuated ERK1/2 activation results in 1) reduced levels of Sp-1, a transcription factor that induces IL-10 expression in monocytes, and 2) impaired H3S10 phosphorylation of the IL10 promoter, an activating epigenetic mark. The pro-inflammatory cytokines tumor necrosis factor (TNF)α and IL-6 are not negatively affected, resulting in an imbalance towards pro-inflammatory cytokines. Thus, impaired ERK1/2 signaling with subsequently reduced Sp-1 expression and H3S10 phosphorylation of the IL10 promoter may centrally contribute to the pathophysiology of CRMO.
authors.affiliation: Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
authors.forename: Sigrun R
authors.initials: SR
authors.lastname: Hofmann
authors.forename: Henner
authors.initials: H
authors.lastname: Morbach
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwarz
authors.forename: Angela
authors.initials: A
authors.lastname: Rösen-Wolff
authors.forename: Hermann J
authors.initials: HJ
authors.lastname: Girschick
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hedrich
mesh_terms: D002843:Chromatin / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000235:genetics* / Q000276:immunology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010019:Osteomyelitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D002843:Chromatin; C508609:IL10 protein, human; D015850:Interleukin-6; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D011494:Protein Kinases; C065999:Sp1 kinase; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3