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

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, bifurca...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2016-06, Vol.6 (1), p.28845-28845, Article 28845
Main Authors: Hachiya, Rumi, Shiihashi, Takuya, Shirakawa, Ibuki, Iwasaki, Yorihiro, Matsumura, Yoshihiro, Oishi, Yumiko, Nakayama, Yukiteru, Miyamoto, Yoshihiro, Manabe, Ichiro, Ochi, Kozue, Tanaka, Miyako, Goda, Nobuhito, Sakai, Juro, Suganami, Takayoshi, Ogawa, Yoshihiro
Format: Article
Language:English
Subjects:
13
13/21
13/95
38/15
38/89
38/90
631/250/256/2516
64/60
692/163/2743/393
692/420/256/2516
Chemokines
Cytokines
Endotoxins
Epigenetics
Genes
Humanities and Social Sciences
Immune system
Lipids
Metabolism
multidisciplinary
Ontology
Science
Transcription factors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep28845