Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation
2011; Springer Nature; Volume: 31; Issue: 13 Linguagem: Inglês
10.1038/onc.2011.353
ISSN1476-5594
AutoresEsteban N. Gurzov, Jenny Barthson, Ihsane Marhfour, Fernanda Ortis, Najib Naamane, Mariana Igoillo‐Esteve, Conny Gysemans, Chantal Mathieu, Shigetaka Kitajima, Piero Marchetti, Torben F. Ørntoft, Latifa Bakiri, Erwin F. Wagner, Décio L. Eizirik,
Tópico(s)Diabetes Management and Research
ResumoDestruction 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.
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