Faculty Collaboration Database

N-terminal BET bromodomain inhibitors disrupt a BRD4-p65 interaction and reduce inducible nitric oxide synthase transcription in pancreatic β-cells. Front Endocrinol (Lausanne) 2022;13:923925

Date

10/01/2022

Pubmed ID

36176467

Pubmed Central ID

PMC9513428

DOI

10.3389/fendo.2022.923925

Scopus ID

2-s2.0-85138892468 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

Chronic inflammation of pancreatic islets is a key driver of β-cell damage that can lead to autoreactivity and the eventual onset of autoimmune diabetes (T1D). In the islet, elevated levels of proinflammatory cytokines induce the transcription of the inducible nitric oxide synthase (iNOS) gene, NOS2, ultimately resulting in increased nitric oxide (NO). Excessive or prolonged exposure to NO causes β-cell dysfunction and failure associated with defects in mitochondrial respiration. Recent studies showed that inhibition of the bromodomain and extraterminal domain (BET) family of proteins, a druggable class of epigenetic reader proteins, prevents the onset and progression of T1D in the non-obese diabetic mouse model. We hypothesized that BET proteins co-activate transcription of cytokine-induced inflammatory gene targets in β-cells and that selective, chemotherapeutic inhibition of BET bromodomains could reduce such transcription. Here, we investigated the ability of BET bromodomain small molecule inhibitors to reduce the β-cell response to the proinflammatory cytokine interleukin 1 beta (IL-1β). BET bromodomain inhibition attenuated IL-1β-induced transcription of the inflammatory mediator NOS2 and consequent iNOS protein and NO production. Reduced NOS2 transcription is consistent with inhibition of NF-κB facilitated by disrupting the interaction of a single BET family member, BRD4, with the NF-κB subunit, p65. Using recently reported selective inhibitors of the first and second BET bromodomains, inhibition of only the first bromodomain was necessary to reduce the interaction of BRD4 with p65 in β-cells. Moreover, inhibition of the first bromodomain was sufficient to mitigate IL-1β-driven decreases in mitochondrial oxygen consumption rates and β-cell viability. By identifying a role for the interaction between BRD4 and p65 in controlling the response of β-cells to proinflammatory cytokines, we provide mechanistic information on how BET bromodomain inhibition can decrease inflammation. These studies also support the potential therapeutic application of more selective BET bromodomain inhibitors in attenuating β-cell inflammation.

Author List

Nord JA, Wynia-Smith SL, Gehant AL, Jones Lipinski RA, Naatz A, Rioja I, Prinjha RK, Corbett JA, Smith BC

Authors

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin
Rachel Jones Lipinski Research Scientist I in the Biochemistry department at Medical College of Wisconsin
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
Sarah L. Wynia Smith Research Scientist II in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cytokines
Diabetes Mellitus, Type 1
Inflammation
Inflammation Mediators
Interleukin-1beta
Mice
NF-kappa B
Nitric Oxide
Nitric Oxide Synthase Type II
Nuclear Proteins
Transcription Factors