Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation

Destruction of insulin-producing pancreatic beta-cells by local autoimmune inflammation is a hallmark of type 1 diabetes. Histochemical analysis of pancreases from non-obese diabetic mice indicated activation of the transcription factor JunB/AP-1 (activator protein-1) after autoimmune infiltration of the islets. In vitro studies demonstrated that the cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma induce JunB expression as a protective mechanism against apoptosis in both human and rodent beta-cells. The gene network affected was studied by microarray analysis showing that JunB regulates nearly 20% of the cytokine-modified beta-cell genes, including the transcription factor ATF3. Direct transcriptional induction of ATF3 by JunB is a key event for beta-cell survival after TNF-alpha + IFN-gamma treatment. Moreover, pharmacological upregulation of JunB/ATF3 via increased cAMP protected rodent primary beta-cells and human islet cells against pro-inflammatory mediators. These results were confirmed in genetically modified islets derived from Ubi-JunB transgenic mice. Our findings identify ATF3 as a novel downstream target of JunB in the survival mechanism of beta-cells under inflammatory stress. Oncogene (2012) 31, 1723-1732; doi:10.1038/onc.2011.353; published online 15 August 2011