BET bromodomain inhibitors attenuate transcription of a subset of IL-1-induced NF-κB target genes that promote inflammation in β-cells

Cytokine-stimulated transcription of NF-κB target genes is linked to the development of multiple inflammatory and autoimmune diseases. Inhibitors of bromodomain and extraterminal domain (BET) epigenetic reader proteins attenuate inflammatory gene transcription and delay the onset of several inflammatory diseases, including autoimmune diabetes. Our previous studies showed that BET bromodomain inhibitors disrupt the interaction between BET family member BRD4 and NF-κB transcription factor p65 in β-cells, thus attenuating cytokine-stimulated NF-κB-dependent gene and functional changes. However, the role of NF-κB in developing inflammatory disease is controversial, as NF-κB inhibition can promote disease progression in some contexts. NF-κB target genes play both physiological and pathophysiological roles in regulating the cellular response to cytokines. Here, using cytokine-stimulated pancreatic β-cells as an inflammatory disease model, we show that NF-κB-dependent gene products that participate in inflammation are sensitive to BET bromodomain inhibition. In contrast, gene products that maintain cellular homeostasis or protect β-cells from stressors are largely insensitive to BET bromodomain inhibition. These studies define a novel and selective role for BET bromodomain-containing proteins in regulating inflammatory gene activation.核因子κB（NF-κB）靶基因的细胞因子刺激型转录，与多种炎症性及自身免疫性疾病的发生发展密切相关。溴结构域与额外末端结构域（BET）表观阅读蛋白抑制剂可减弱炎症基因转录，并延缓包括自身免疫性糖尿病在内的多种炎症性疾病的发作进程。我们既往的研究表明，BET溴结构域抑制剂可破坏胰岛β细胞中BET家族成员BRD4与核因子κB转录因子p65的相互作用，进而削弱细胞因子刺激下核因子κB依赖型基因及功能的改变。然而，核因子κB在炎症性疾病发生发展中的作用尚存争议，因为在部分情境下，核因子κB抑制反而会促进疾病进展。核因子κB靶基因在调控细胞对细胞因子的应答过程中，同时发挥生理及病理生理作用。本研究以细胞因子刺激的胰腺β细胞作为炎症性疾病模型，证实参与炎症反应的核因子κB依赖型基因产物对BET溴结构域抑制剂敏感。与之相反，维持细胞稳态或保护胰岛β细胞免受应激原损伤的基因产物，在很大程度上对BET溴结构域抑制剂不敏感。本研究明确了含BET溴结构域蛋白在调控炎症基因激活过程中的全新选择性作用。