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

• Published in: Oncogene Vol. 31; no. 13; pp. 1723 - 1732
• Main Authors: Gurzov, E N, Barthson, J, Marhfour, I, Ortis, F, Naamane, N, Igoillo-Esteve, M, Gysemans, C, Mathieu, C, Kitajima, S, Marchetti, P, Ørntoft, T F, Bakiri, L, Wagner, E F, Eizirik, D L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.03.2012; Nature Publishing Group
• Subjects: Activating transcription factor 3; Activating Transcription Factor 3 - metabolism; Activator protein 1; Analysis; Animals; Apoptosis; Beta cells; Cell Biology; Cell survival; Complications and side effects; Cyclic AMP; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - metabolism; DNA microarrays; Gene Knockdown Techniques; Genetic aspects; Human Genetics; Humans; Inflammation; Inflammation - metabolism; Insulin; Insulin-Secreting Cells - metabolism; Interferon; Internal Medicine; Islet cells; Islets of Langerhans; JunB protein; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Inbred NOD; Mice, Transgenic; Oncology; original-article; Pancreas; Pancreatic beta cells; Physiological aspects; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; Risk factors; Signal Transduction; Stress; Transcription activation; Transcription factors; Transgenic mice; Tumor necrosis factor; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Type 1 diabetes; γ-Interferon; United States; apoptosis; type 1 diabetes; JunB; ATF3; pancreatic β cells
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.353

Destruction of insulin-producing pancreatic β-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)-α and interferon (IFN)-γ induce JunB expression as a protective mechanism against apoptosis in both human and rodent β-cells. The gene network affected was studied by microarray analysis showing that JunB regulates nearly 20% of the cytokine-modified β-cell genes, including the transcription factor ATF3. Direct transcriptional induction of ATF3 by JunB is a key event for β-cell survival after TNF-α+IFN-γ treatment. Moreover, pharmacological upregulation of JunB/ATF3 via increased cAMP protected rodent primary β-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 β-cells under inflammatory stress.