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 expression1,2,3,4. 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 expression5,6,7,8,9,10. 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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gene Expression Omnibus
Protein Data Bank
Crystal structure of the first bromodomain of human BRD4 in complex with I-BET inhibitor was deposited in the RCSB Protein Data Bank with PDB ID code 3P5O. Microarray and ChIP sequencing results were deposited in GEO with GEO accession codes GSE21764 and GSE21910, respectively.
We would like to acknowledge R. Grimley and C. Patel for supplying FRET data and R. Woodward, C. Delves, E. Jones and P. Holmes for protein production. J. Witherington, N. Smithers, S. Baddeley, J. Seal and L. Cutler provided compound selectivity and pharmacokinetics data. G. Krysa, O. Mirguet and R. Gosmini contributed to the discovery, development and characterization of the compound. We thank R. Anthony and S. McCleary for assistance with animal models, R. Gejman for bioinformatics analysis of gene expression kinetics and A. Santana and T. Chapman for technical assistance. We would like to thank C. Nathan, R. Medzhitov, S. Rudensky and S. Smale for helpful discussions and S. Sampath for his contribution to the concept of ‘histone mimicry’. R.C. is supported by an NIH KL2 Career Development Award and I.M. is supported by the American Italian Cancer Foundation. K.L.J. is supported by the National Health and Medical Research Council of Australia and is currently a Rockefeller University Women in Science Fellow.
The file contains Supplementary Figures 1-14 with legends, Supplementary Tables 1-3, Supplementary Methods and additional references.