JunB inhibits ER stress and apoptosis in pancreatic beta cells

Abstract

Cytokines contribute to pancreatic β-cell apoptosis in type 1 diabetes (T1D) by modulation of β-cell gene expression networks. The transcription factor Activator Protein-1 (AR-1) is a key regulator of inflammation and apoptosis. We presently evaluated the function of the AP-1 subunit JunB in cytokine-mediated β-cell dysfunction and death. The cytokines IL-1β+IFN-γ induced cytokine-mediated expression of inducible nitric oxide synthase (iNOS) and endoplasmic reticulum (ER) stress markers, leading to increased apoptosis in an insulin-producing cell line (iNS-1E) and in purified rat primary β-cells. JunB knockdown β-cells and junB-/- fibroblasts were also more sensitive to the chemical ER stressor cyclopiazonic acid (CPA). Conversely, adenoviral-mediated overexpression of JunB diminished iNOS and ER markers expression and protected β-cells from cytokine-induced cell dealth. These findings demonstrate a novel and unexpected role for JunB as a regulator of defense mechanisms against cytokine- and ER stress-mediated apoptosis. © 2008 Gurzov et al.