title: Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation.
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.
authors.affiliation: Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium. egurzov@ulb.ac.be
authors.forename: E N
authors.initials: EN
authors.lastname: Gurzov
authors.forename: J
authors.initials: J
authors.lastname: Barthson
authors.forename: I
authors.initials: I
authors.lastname: Marhfour
authors.forename: F
authors.initials: F
authors.lastname: Ortis
authors.forename: N
authors.initials: N
authors.lastname: Naamane
authors.forename: M
authors.initials: M
authors.lastname: Igoillo-Esteve
authors.forename: C
authors.initials: C
authors.lastname: Gysemans
authors.forename: C
authors.initials: C
authors.lastname: Mathieu
authors.forename: S
authors.initials: S
authors.lastname: Kitajima
authors.forename: P
authors.initials: P
authors.lastname: Marchetti
authors.forename: T F
authors.initials: TF
authors.lastname: Ørntoft
authors.forename: L
authors.initials: L
authors.lastname: Bakiri
authors.forename: E F
authors.initials: EF
authors.lastname: Wagner
authors.forename: D L
authors.initials: DL
authors.lastname: Eizirik
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D016755:Proto-Oncogene Proteins c-jun; D014409:Tumor Necrosis Factor-alpha