Bromodomain protein inhibition protects β-cells from cytokine-induced death and dysfunction via antagonism of NF-κB pathway.

Abstract

Cytokine induced {beta}-cell apoptosis is the major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding underlying mechanisms, few drugs have been translated to protect {beta}-cells in T1D. Epigenetic modulators such as bromodomain-containing BET (Bromo- and Extra-Terminal) proteins are important regulators of immune responses. Pre-clinical studies have demonstrated a protective effect of BET inhibitors in NOD (non-obese diabetes) mouse model of T1D. However, the role of BET proteins in {beta}-cell function in response to cytokines is unknown. Here we demonstrate that I-BET, a BET protein inhibitor, protected {beta}-cells from cytokine induced dysfunction and death. In vivo administration of I-BET to mice exposed to low-dose STZ (streptozotocin), a model of T1D, significantly reduced {beta}-cell apoptosis and preserved {beta}-cell mass, suggesting a cytoprotective function of I-BET. Furthermore, human islets treated with I-BET displayed better glucose stimulated insulin secretion compared to controls, when exposed to cytokines. Mechanistically, RNA-Seq analysis revealed I-BET treatment suppressed pathways involved in apoptosis, including NF-kB signaling, while maintaining the expression of genes critical for {beta}-cell function, such as Pdx1 and Ins1. Taken together, this study demonstrates that I-BET is effective in protecting {beta}-cells from cytokine-induced dysfunction and apoptosis, and may have potential therapeutic values in T1D.