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Sci Rep. 2016 Jun 28;6:28845. doi: 10.1038/srep28845.

The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages.

Author information

1
Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
2
Department of Life Science and Medical Bio-Science, School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsu-cho, Shinjuku-ku,Tokyo, 162-8480, Japan.
3
Department of Organ Network and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
4
Division of Metabolic Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
5
Department of Cellular and Molecular Medicine, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
6
Department of Cardiovascular Medicine, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
7
Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-0873, Japan.
8
Department of Aging Research, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan.
9
Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.
10
Japan Science and Technology Agency, PRESTO, 7 Goban-cho, Chiyoda-ku, Tokyo, 102-0076, Japan.
11
Japan Agency for Medical Research and Development, AMED-CREST, 1-7-1 Otemachi, Chiyoda-ku, Tokyo, 100-0004, Japan.
12
Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, 464-8601, Japan.

Abstract

Proinflammatory cytokine production in macrophages involves multiple regulatory mechanisms, which are affected by environmental and intrinsic stress. In particular, accumulating evidence has suggested epigenetic control of macrophage differentiation and function mainly in vitro. SET domain, bifurcated 1 (Setdb1, also known as Eset) is a histone 3 lysine 9 (H3K9)-specific methyltransferase and is essential for early development of embryos. Here we demonstrate that Setdb1 in macrophages potently suppresses Toll-like receptor 4 (TLR4)-mediated expression of proinflammatory cytokines including interleukin-6 through its methyltransferase activity. As a molecular mechanism, Setdb1-deficiency decreases the basal H3K9 methylation levels and augments TLR4-mediated NF-κB recruitment on the proximal promoter region of interleukin-6, thereby accelerating interleukin-6 promoter activity. Moreover, macrophage-specific Setdb1-knockout mice exhibit higher serum interleukin-6 concentrations in response to lipopolysaccharide challenge and are more susceptible to endotoxin shock than wildtype mice. This study provides evidence that the H3K9 methyltransferase Setdb1 is a novel epigenetic regulator of proinflammatory cytokine expression in macrophages in vitro and in vivo. Our data will shed insight into the better understanding of how the immune system reacts to a variety of conditions.

PMID:
27349785
PMCID:
PMC4924096
DOI:
10.1038/srep28845
[Indexed for MEDLINE]
Free PMC Article

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