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

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• 作者：Sigrun R. Hofmann ; Henner Morbach ; Tobias Schwarz ; Angela R?sen-Wolff ; Hermann J. Girschick ; Christian M. Hedrich
• 关键词：CRMO ; CNO ; IL-10 ; Chromatin ; Sp-1 ; Histone
• 刊名：Clinical Immunology
• 出版年：2012
• 出版时间：October, 2012
• 年：2012
• 卷：145
• 期：1
• 页码：69-76
• 全文大小：562 K

文摘

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)¦Á 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.