BET bromodomain inhibitors diminish IL‐1B‐induced transcription of NF‐κB target genes

Abstract

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic β-cells, thought to be a result of chronic inflammation of pancreatic islets. Elevated proinflammatory cytokine levels in the islet results in increased nitric oxide production through increased transcription of inducible nitric oxide synthase (iNOS), reduced glucose responsiveness, and ultimately selective destruction of insulin-producing β-cells. The exact causes of T1D are poorly understood and although genetic predisposition is a factor, low concordance rates of autoimmune diabetes among monozygotic twins suggests an, as yet undetermined role for epigenetic factors. Recent studies have shown that epigenetic regulatory proteins contribute to the onset and progression of autoimmune diabetes. The bromodomain and extraterminal domain (BET) family of proteins (Brd2, Brd3, Brd4 and BrdT) have emerged as promising drug targets for a wide variety of diseases. Bromodomain-containing proteins are epigenetic “readers” of histone acetylation and we hypothesize they regulate proinflammatory cytokine induced transcription in β-cells. Uniquely, the BET family proteins contain two bromodomains (BD1 and BD2), which affords BET proteins the capacity to simultaneously bind two acetylated histones and/or other nuclear proteins such as DNA-binding factors to modulate transcription in a cell-type specific manner. Here, we show that BET bromodomain inhibitors decrease the β-cell response to proinflammatory cytokines in insulinoma β-cell line (INS832/13) and primary rat islets. We found that BET inhibitors mitigated cytokine-induced transcription of inflammatory mediators, including iNOS, which is known to damage β-cells. This decrease is mediated through inhibition of the NF-κB pathway by BET inhibitors. Furthermore, using knockdown of BET proteins in insulinoma β-cell lines, we identified key mechanisms through which this altered transcriptional profile occurs. This work provides important mechanistic insights into the disease onset and progression of autoimmune diabetes for which current therapies are ineffective.