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

Oncogene volume 31, pages 1723–1732 (2012)Cite this article

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.

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Acknowledgements

We thank MA Neef, G Vandenbroeck, M Urbain, R Makhnas, AE Musuaya and S Mertens of the Laboratory of Experimental Medicine (Université Libre de Bruxelles, Brussels, Belgium) for excellent technical support, and Drs L Marselli and L Ladrière for help with human islet preparations. This work was supported by grants from the Communauté Française de Belgique–Actions de Recherche Concertées (ARC), Fonds National de la Recherche Scientifique (FNRS) Belgium, the Belgium Program on Interuniversity Poles of Attraction initiated by the Belgium State (IUAP P6/40), the Juvenile Diabetes Research Foundation International (JDRFI Grant 17-2009-106) and the European Union (project Naimit, in the Framework Programme 7 of the European Community). ENG was supported by an EMBO long-term fellowship. CG and CM were supported by a postdoctoral and senior clinical scholarship from the FWO Vlaanderen, respectively.

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Authors and Affiliations

  1. Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Brussels, Belgium

    E N Gurzov, J Barthson, I Marhfour, F Ortis, N Naamane, M Igoillo-Esteve & D L Eizirik

  2. Laboratory of Experimental Medicine Endocrinology (LEGENDO), Faculty of Medicine, Katholieke Universiteit Leuven-KU Leuven, Leuven, Belgium

    C Gysemans & C Mathieu

  3. Department of Biochemical Genetics, Medical Research Institute and Laboratory of Genome Structure and Regulation, School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan

    S Kitajima

  4. Department of Endocrinology and Metabolism, Metabolic Unit - University of Pisa, Ospedale Cisanello, Pisa, Italy

    P Marchetti

  5. and the Department of Molecular Medicine, CMO Aros Applied Biotechnology AS, Science Park Skejby Brendstrupgaardsvej, Aarhus, Denmark, Aarhus University Hospital, Aarhus, Denmark

    T F Ørntoft

  6. Banco Bilbao Vizcaya Argentaria (BBVA)-Foundation, Cancer Cell Biology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

    L Bakiri & E F Wagner

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Correspondence to E N Gurzov.

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Gurzov, E., Barthson, J., Marhfour, I. et al. Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation. Oncogene 31, 1723–1732 (2012). https://doi.org/10.1038/onc.2011.353

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