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Cytokine Production by Suppressing Tollip Promotes TLR-Triggered

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Cytokine Production by Suppressing Tollip Promotes TLR-Triggered Histone Lysine Methyltransferase Ezh1 Promotes TLR-Triggered Inflammatory Cytokine Production by Suppressing Tollip This information is current as Yiqi Liu, Qian Zhang, Yuanyuan Ding, Xia Li, Dezhi Zhao, of September 27, 2021. Kai Zhao, Zhenhong Guo and Xuetao Cao J Immunol published online 16 February 2015 http://www.jimmunol.org/content/early/2015/02/16/jimmun ol.1402087 Downloaded from Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on September 27, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 16, 2015, doi:10.4049/jimmunol.1402087 The Journal of Immunology Histone Lysine Methyltransferase Ezh1 Promotes TLR-Triggered Inflammatory Cytokine Production by Suppressing Tollip Yiqi Liu,*,†,1 Qian Zhang,†,1 Yuanyuan Ding,* Xia Li,* Dezhi Zhao,* Kai Zhao,† Zhenhong Guo,† and Xuetao Cao*,†,‡ 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-a, and IFN-b, in DCs and macrophages. Accordingly, TLR-activated Downloaded from 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2015, 194: 000–000. pon recognition of invading pathogens, the innate im- inflammation and tissue damage, and even multiple organ failure. mune response is efficiently initiated against the infec- Thus, negative regulation of the innate response attracts much tion. Once the invading pathogens have been eliminated, attention, and many negative regulators of the innate response U by guest on September 27, 2021 the immune response must be tightly regulated to be at the ap- have been reported to play important roles in maintaining the propriate level to maintain the homeostasis of the immune system. balance between the immune response and inflammation (1). If regulation of the innate immune response is out of control, It was shown that invading pathogens may develop a strategy to overproduction of inflammatory cytokines may lead to excessive use the host negative regulators to downregulate the host defense and, thereby, escape the innate response, leading to chronic infections. Suppressor of cytokine signaling 1 can be induced by *Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; †National Key Laboratory of Medical Molecular Biology and De- various pathogenic components, which restricts activation of partment of Immunology, Institute of Basic Medical Sciences, Chinese Academy of macrophage through repressing the JAK/STAT and TLR/NF-kB Medical Sciences, Beijing 100005, China; and ‡National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, pathways (2). Ebola virus VP35 protein was shown to inhibit IFN Shanghai 200433, China production in innate immune cells by promoting sumoylation of 1Y.L. and Q.Z. contributed equally to this work. IRF7 via the E3 ligase PIAS1 (3). Siglec-G, selectively upregu- Received for publication August 13, 2014. Accepted for publication January 15, lated by the RNA virus, can recruit SHP2 and the E3 ubiquitin 2015. ligase c-Cbl to bind RIG-I and then promote RIG-I degradation This work was supported by grants from the National Key Basic Research Program of via ubiquitination, attenuating the innate response to RNA virus China (2013CB530502) and the National Natural Science Foundation of China infection (4). Therefore, the expression level and function of (31390431, 81230074, 81123006, 31200654, and 31270966). negative regulators are well-tuned to maintain homeostasis of the The sequences presented in this article have been submitted to the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/genbank) under accession number immune system. A better understanding of the mechanisms for the GSE60307. negative regulation of the innate response will benefit the design Address correspondence and reprint requests to Prof. Xuetao Cao, Institute of Im- of immunotherapy for the control of inflammatory disorders or munology, Zhejiang University School of Medicine, Hangzhou 310058, China. autoimmune diseases. New negative regulators and their under- E-mail address: [email protected] lying mechanism need to be identified. Abbreviations used in this article: BMDC, bone marrow–derived DC; ChIP, chroma- TLRs are important components of the innate immune response, tin immunoprecipitation; DC, dendritic cell; EZHI vector, full-length Ezh1 vector; EZH1-DSET, SET domain–depleted Ezh1 vector; H3K27, histone H3 lysine 27; which initiates the elimination of invading micro-organisms H3K27me2, dimethylation of H3K27; H3K27me3, trimethylation of H3K27; IRAK, through the induction of inflammatory molecules, including IL-1R–associated kinase; KDM, lysine demethylase; KMT, lysine methyltrans- ferase; ODN, oligodeoxynucleotide; PGN, peptidoglycan; Poly(I:C), polyinosinic- cytokines, chemokines, and other antimicrobial factors (5). TLRs polycytidylic acid; qPCR, quantitative PCR; RNA-seq, RNA sequencing; RPKM, activate multiple pathways rapidly upon recognizing structurally reads per kilobase per million reads; siRNA, small interfering RNA; Tollip, Toll- conserved lipid, carbohydrate, peptide, and nucleic acid molecules interacting protein; TSS, transcription start site. that are components of microbial pathogens. The transcription of Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 hundreds of genes is induced during the immune response acti- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1402087 2 EZH1 PROMOTES TLR RESPONSE VIA TARGETING TOLLIP vated by TLR signals. To determine how these genes are orga- In this study, we investigated the role of Ezh1 in the regulation of nized and transcripted, much attention has been paid to the tran- the innate immune response in DCs and macrophages and found scription factors and the modulators in the activated signaling that it promotes TLR-triggered inflammatory cytokine production pathways. by suppressing the expression of Toll-interacting protein (Tollip), In recent years, more and more evidence has shown the im- the key negative regulator of TLR signaling. portance of epigenetic regulation of the immune response. Epi- genetic changes influence gene expression without altering the Materials and Methods DNA sequence. DNA methylation, histone modification, and Mice and reagents microRNA-associated gene silencing are key epigenetic mecha- C57BL/6J mice were obtained from Joint Ventures Sipper BK Experimental nisms. Recently, the DNA-methylation adaptor Uhrf1 was shown to Animal (Shanghai, China). All animal experiments were performed in promote proliferation and functional maturation of colonic regu- accordance with the National Institutes of Health Guide for the Care and latory T cells (6). Histone deacetylase 2 was shown to regulate the Use of Laboratory Animals, with the approval of the Scientific Investiga- phenotype of myeloid-derived suppressor cells in cancer through tion Board of Second Military Medical University. LPS (0111:B4) was from Sigma-Aldrich. Polyinosinic-polycytidylic acid [Poly(I:C)] was from histone acetylation (7). Our previous study showed that death Calbiochem. Peptidoglycan (PGN; Staphylococcus aureus) was from domain–associated protein 6 selectively represses IL-6 expression Sigma-Aldrich. CpG-oligodeoxynucleotide (ODN) was synthesized and via histone acetylation at the IL-6 promoter region (8). Epigenetic
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