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

Abstract

Disruption of the interaction of bromo and extra terminal (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 (pTEFb) 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-γ, IFN-γ, IL-4 and IL-10 that 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. Interferon-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 expand the understanding of the inhibitory and potentially selective immunosuppressive effects of inhibiting BET proteins.

Molecular control of activation and priming in macrophages

“…Specific modifications are associated with different functional states. Although the precise functional role of different chromatin modifications and their readers in this specific and other responses is only partially understood 45 , evidence for a direct role of chromatin in regulating macrophage responses has been reported 46, 47 . Promoters are characterized by high levels of trimethylation of histone H3 lysine 4 (H3K4me3) in comparison to mono- or di-methylation of this residue, whereas enhancers exhibit high levels of monomethylation of H3 lysine 4 (H3K4me1) in comparison to tri-methylation.…”

Imiquimod-induced psoriasis-like skin inflammation is suppressed by BET bromodomain inhibitor in mice through RORC/IL-17A pathway modulation

“…The bromodomain and extraterminal domain (BET) family is a distinct group of bromodomain proteins that in mammals includes BRD2, BRD3, BRD4, and histones. This feature of BET proteins confers them the ability to govern histone acetylation-dependent transcriptional regulation [11][12].…”

The therapeutic potential of epigenetic manipulation during infectious diseases

“…More recently, these results have been reproduced in primary human macrophages. The authors demonstrated that I-BET151 led to decreased IFN responses following TLR4 and TNF-α stimulations (Chan et al, 2015). …”