Format

Send to

Choose Destination
Eur J Immunol. 2015 Jan;45(1):287-297. doi: 10.1002/eji.201444862. Epub 2014 Dec 1.

BET bromodomain inhibition suppresses transcriptional responses to cytokine-Jak-STAT signaling in a gene-specific manner in human monocytes.

Author information

1
Arthritis and Tissue Degeneration Program and David Z. Rosensweig Center for Genomics Research, Hospital for Special Surgery, New York, New York, USA.
2
GlaxoSmithKline, Epinova DPU, Stevenage, United Kingdom.
3
Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA.
#
Contributed equally

Abstract

Disruption of the interaction of bromo and extraterminal (BET) proteins with acetylated histones using small molecule inhibitors suppresses Myc-driven cancers and TLR-induced inflammation in mouse models. The predominant mechanism of BET inhibitor action is to suppress BET-mediated recruitment of positive transcription elongation factor b and, thus, transcription elongation. We investigated the effects of BET inhibitor I-BET151 on transcriptional responses to TLR4 and TNF in primary human monocytes and also on responses to cytokines IFN-β, IFN-γ, IL-4, and IL-10, which activate the JAK-STAT signaling pathway and are important for monocyte polarization and inflammatory diseases. I-BET151 suppressed TLR4- and TNF-induced IFN responses by diminishing both autocrine IFN-β expression and transcriptional responses to IFN-β. I-BET151 inhibited cytokine-induced transcription of STAT targets in a gene-specific manner without affecting STAT activation or recruitment. This inhibition was independent of Myc or other upstream activators. IFN-stimulated gene transcription is regulated primarily at the level of transcription initiation. Accordingly, we found that I-BET151 suppressed the recruitment of transcriptional machinery to the CXCL10 promoter and an upstream enhancer. Our findings suggest that BET inhibition reduces inflammation partially through suppressing cytokine activity and expands the understanding of the inhibitory and potentially selective immunosuppressive effects of inhibiting BET proteins.

KEYWORDS:

Chromatin remodeling; Cytokines; Inflammation; Monocytes; Transcription

PMID:
25345375
PMCID:
PMC4293348
DOI:
10.1002/eji.201444862
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center