Suppression of inflammation by a synthetic histone mimic

被引:1250
作者
Nicodeme, Edwige [2 ]
Jeffrey, Kate L. [1 ]
Schaefer, Uwe [1 ]
Beinke, Soren [3 ]
Dewell, Scott [4 ]
Chung, Chun-wa [5 ]
Chandwani, Rohit [1 ]
Marazzi, Ivan [1 ]
Wilson, Paul [5 ]
Coste, Herve [2 ]
White, Julia [5 ]
Kirilovsky, Jorge [2 ]
Rice, Charles M. [6 ]
Lora, Jose M. [3 ]
Prinjha, Rab K. [3 ]
Lee, Kevin [3 ]
Tarakhovsky, Alexander [1 ]
机构
[1] Rockefeller Univ, Lab Lymphocyte Signaling, New York, NY 10065 USA
[2] Ctr Res GSK, F-91140 Villebon Sur Yvette, France
[3] GlaxoSmithKline, Med Res Ctr, Epinova DPU, Immunoinflammat Ctr Excellence Drug Discovery, Stevenage SG1 2NY, Herts, England
[4] Rockefeller Univ, Genom Resource Ctr, New York, NY 10065 USA
[5] GlaxoSmithKline R&D, Med Res Ctr, Stevenage SG1 2NY, Herts, England
[6] Rockefeller Univ, Lab Virol & Infect Dis, New York, NY 10065 USA
基金
英国医学研究理事会;
关键词
BROMODOMAIN PROTEIN BRD4; TRANSCRIPTIONAL ELONGATION; GENE-EXPRESSION; BINDING MODULES; P-TEFB; CHROMATIN; COMPLEXES; MACHINES;
D O I
10.1038/nature09589
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression(1-4). Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression(5-10). Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.
引用
收藏
页码:1119 / 1123
页数:5
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