NDLI: Histone lysine methyltransferase Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing Tollip.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Zhao, Dezhi Liu, Yiqi Guo, Zhenhong Ding, Yuanyuan Zhao, Kai Zhang, Qian Li, Xia Cao, Xuetao
Description	Author Affiliation: Liu Y ( Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China); Zhang Q ( National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China); Ding Y ( Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China); Li X ( Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China); Zhao D ( Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China); Zhao K ( National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China); Guo Z ( National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China); Cao X ( Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China)
Abstract	Histone modifications play critical roles in the regulation of gene expression; however, their roles in the regulation of the innate response remain to be fully investigated. Using transcriptome analysis of mouse immature dendritic cells (DCs) and LPS-induced mature DCs, we identified that Ezh1 was the most upregulated histone methyltransferase during DC maturation. In this study, we investigated the role of Ezh1 in regulating the innate immune response. We found that silencing of Ezh1 significantly suppressed TLR-triggered production of cytokines, including IL-6, TNF- , and IFN-ß, in DCs and macrophages. Accordingly, TLR-activated signaling pathways were impaired in Ezh1-silenced macrophages. By transcriptome analysis of Ezh1-silenced macrophages, we found that Toll-interacting protein (Tollip), one well-known negative regulator of TLR signaling, was upregulated. Silencing of Tollip rescued TLR-triggered cytokine production in Ezh1-silenced macrophages. The SET domain of Ezh1 is essential for its enhancing effect on the TLR-triggered innate immune response and downstream signaling, indicating that Ezh1 promotes a TLR-triggered innate response through its lysine methyltransferase activity. Finally, Ezh1 was found to suppress the transcription of Tollip by directly targeting the proximal promoter of tollip and maintaining the high level of trimethylation of histone H3 lysine 27 there. Therefore, Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing the TLR negative regulator Tollip, contributing to full activation of the innate immune response against invading pathogens.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	6
Volume Number	194
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2015-03-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cytokines Immunology Intracellular Signaling Peptides And Proteins Polycomb Repressive Complex 2 Toll-like Receptors Animals Blotting, Western Cells, Cultured Genetics Metabolism Dendritic Cells Histones Immunity, Innate Inflammation Mediators Lipopolysaccharides Pharmacology Lysine Macrophages Methylation Mice, Inbred C57bl Oligodeoxyribonucleotides Poly I-c Promoter Regions, Genetic Protein Binding Rna Interference Reverse Transcriptase Polymerase Chain Reaction Agonists Transcriptome Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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