Attenuated TLR4/MAPK signaling in monocytes from patients with CRMO results in impaired IL-10 expression

Sigrun R Hofmann; Henner Morbach; Tobias Schwarz; Angela Rösen-Wolff; Hermann J Girschick; Christian M Hedrich

doi:10.1016/j.clim.2012.07.012

Attenuated TLR4/MAPK signaling in monocytes from patients with CRMO results in impaired IL-10 expression

Clin Immunol. 2012 Oct;145(1):69-76. doi: 10.1016/j.clim.2012.07.012. Epub 2012 Aug 4.

Authors

Sigrun R Hofmann¹, Henner Morbach, Tobias Schwarz, Angela Rösen-Wolff, Hermann J Girschick, Christian M Hedrich

Affiliation

¹ Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.

PMID: 22940633
DOI: 10.1016/j.clim.2012.07.012

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chromatin / genetics
Chromatin / immunology
Gene Expression
Humans
Interleukin-10 / genetics
Interleukin-10 / immunology
Interleukin-10 / metabolism*
Interleukin-6 / biosynthesis
Interleukin-6 / immunology
MAP Kinase Signaling System / genetics*
MAP Kinase Signaling System / immunology
Mitogen-Activated Protein Kinase 1 / genetics
Mitogen-Activated Protein Kinase 1 / immunology
Mitogen-Activated Protein Kinase 1 / metabolism*
Mitogen-Activated Protein Kinase 3 / genetics
Mitogen-Activated Protein Kinase 3 / immunology
Mitogen-Activated Protein Kinase 3 / metabolism*
Monocytes / immunology
Monocytes / metabolism
Osteomyelitis / genetics
Osteomyelitis / immunology
Osteomyelitis / metabolism*
Phosphorylation
Primary Cell Culture
Promoter Regions, Genetic
Protein Kinases / genetics
Protein Kinases / immunology
Protein Kinases / metabolism
Toll-Like Receptor 4 / genetics
Toll-Like Receptor 4 / immunology
Toll-Like Receptor 4 / metabolism*
Tumor Necrosis Factor-alpha / biosynthesis
Tumor Necrosis Factor-alpha / immunology

Substances

Chromatin
IL10 protein, human
Interleukin-6
TLR4 protein, human
Toll-Like Receptor 4
Tumor Necrosis Factor-alpha
Interleukin-10
Protein Kinases
Sp1 kinase
MAPK1 protein, human
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3

Supplementary concepts

Chronic recurrent multifocal osteomyelitis