Bromodomain Protein Inhibition Protects β-Cells from Cytokine-Induced Death and Dysfunction via Antagonism of NF-κB Pathway
Vinny Negi,
Jeongkyung Lee,
Varun Mandi,
Joseph Danvers,
Ruya Liu,
Eliana M. Perez-Garcia,
Feng Li,
Rajaganapati Jagannathan,
Ping Yang,
Domenic Filingeri,
Amit Kumar,
Ke Ma,
Mousumi Moulik,
Vijay K. Yechoor
Affiliations
Vinny Negi
Diabetes and Beta Cell Biology Center, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15213, USA
Jeongkyung Lee
Diabetes and Beta Cell Biology Center, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15213, USA
Varun Mandi
Diabetes and Beta Cell Biology Center, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15213, USA
Joseph Danvers
Diabetes and Beta Cell Biology Center, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15213, USA
Ruya Liu
Diabetes and Beta Cell Biology Center, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15213, USA
Eliana M. Perez-Garcia
Diabetes and Beta Cell Biology Center, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15213, USA
Feng Li
Diabetes and Beta Cell Biology Center, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15213, USA
Rajaganapati Jagannathan
Division of Cardiology, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA
Ping Yang
Diabetes and Beta Cell Biology Center, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15213, USA
Domenic Filingeri
Diabetes and Beta Cell Biology Center, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15213, USA
Amit Kumar
Diabetes and Beta Cell Biology Center, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15213, USA
Ke Ma
Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
Mousumi Moulik
Division of Cardiology, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA
Vijay K. Yechoor
Diabetes and Beta Cell Biology Center, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15213, USA
Cytokine-induced β-cell apoptosis is a major pathogenic mechanism in type 1 diabetes (T1D). Despite significant advances in understanding its underlying mechanisms, few drugs have been translated to protect β-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 an NOD (non-obese diabetes) mouse model of T1D. However, the effect of BET protein inhibition on β-cell function in response to cytokines is unknown. Here, we demonstrate that I-BET, a BET protein inhibitor, protected β-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 β-cell apoptosis, suggesting a cytoprotective function. Mechanistically, I-BET treatment inhibited cytokine-induced NF-kB signaling and enhanced FOXO1-mediated anti-oxidant response in β-cells. RNA-Seq analysis revealed that I-BET treatment also suppressed pathways involved in apoptosis while maintaining the expression of genes critical for β-cell function, such as Pdx1 and Ins1. Taken together, this study demonstrates that I-BET is effective in protecting β-cells from cytokine-induced dysfunction and apoptosis, and targeting BET proteins could have potential therapeutic value in preserving β-cell functional mass in T1D.
