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- Title
Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation.
- 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
- Abstract
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.
- Subjects
PANCREATIC beta cells; INFLAMMATION; TRANSCRIPTION factors; CELLULAR pathology; DIABETES; TUMOR necrosis factors; INTERFERONS; LABORATORY mice
- Publication
Oncogene, 2012, Vol 31, Issue 13, p1723
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2011.353