Suppression of interferon β gene transcription by inhibitors of bromodomain and extra-terminal (BET) family members.

Abstract

PLK (Polo-like kinase) inhibitors, such as BI-2536, have been reported to suppress IFNB (encoding IFNβ, interferon β) gene transcription induced by ligands that activate TLR3 (Toll-like receptor 3) and TLR4. In the present study, we found that BI-2536 is likely to exert this effect by preventing the interaction of the transcription factors IRF3 (interferon-regulatory factor 3) and c-Jun with the IFNB promoter, but without affecting the TBK1 {TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor κB activator]-binding kinase 1}-catalysed phosphorylation of IRF3 at Ser³⁹⁶, the dimerization and nuclear translocation of IRF3 or the phosphorylation of c-Jun and ATF2 (activating transcription factor 2). Although BI-2536 inhibits few other kinases tested, it interacts with BET (bromodomain and extra-terminal) family members and displaces them from acetylated lysine residues on histones. We found that BET inhibitors that do not inhibit PLKs phenocopied the effect of BI-2536 on IFNB gene transcription. Similarly, BET inhibitors blocked the interaction of IRF5 with the IFNB promoter and the secretion of IFNβ induced by TLR7 or TLR9 ligands in the human plasmacytoid dendritic cell line GEN2.2, but without affecting the nuclear translocation of IRF5. We found that the BET family member BRD4 (bromodomain-containing protein 4) was associated with the IFNB promoter and that this interaction was enhanced by TLR3- or TLR4-ligation and prevented by BI-2536 and other BET inhibitors. Our results establish that BET family members are essential for TLR-stimulated IFNB gene transcription by permitting transcription factors to interact with the IFNB promoter. They also show that the interaction of the IFNB promoter with BRD4 is regulated by TLR ligation and that BI-2536 is likely to suppress IFNB gene transcription by targeting BET family members.

• Authors: Nazma Malik, Stefan Vollmer, Sambit Kumar Nanda, Marta Lopez-Pelaez, Alan Prescott, Nathanael Gray, Philip Cohen
• Journal: The Biochemical journal (Biochem J) Vol. 468 Issue 3 Pg. 363-72 (Jun 15 2015) ISSN: 1470-8728 [Electronic] England
• PMID: 25891802 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Author(s).

Chemical References

• Antimitotic Agents
• BI 2536
• BRD4 protein, human
• Brd4 protein, mouse
• Cell Cycle Proteins
• Interferon Regulatory Factor-3
• Ligands
• Nuclear Proteins
• Protein Isoforms
• Proto-Oncogene Proteins c-jun
• Pteridines
• Toll-Like Receptor 7
• Toll-Like Receptor 9
• Transcription Factors
• Interferon-beta

Topics

• Animals
• Antimitotic Agents (pharmacology)
• Cell Cycle Proteins
• Cell Line, Transformed
• Dendritic Cells (drug effects, immunology, metabolism)
• Humans
• Interferon Regulatory Factor-3 (antagonists & inhibitors, metabolism)
• Interferon-beta (antagonists & inhibitors, genetics, metabolism)
• Ligands
• Macrophages (drug effects, immunology, metabolism)
• Mice
• Nuclear Proteins (antagonists & inhibitors, metabolism)
• Promoter Regions, Genetic (drug effects)
• Protein Isoforms (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-jun (antagonists & inhibitors, metabolism)
• Pteridines (pharmacology)
• Signal Transduction (drug effects)
• Toll-Like Receptor 7 (metabolism)
• Toll-Like Receptor 9 (metabolism)
• Transcription Factors (antagonists & inhibitors, metabolism)
• Transcription, Genetic (drug effects)