title: Cytokines tumor necrosis factor-α and interferon-γ induce pancreatic β-cell apoptosis through STAT1-mediated Bim protein activation.
abstract: Type 1 diabetes is characterized by local inflammation (insulitis) in the pancreatic islets causing β-cell loss. The mitochondrial pathway of apoptosis is regulated by the balance and interaction between Bcl-2 members. Here we clarify the molecular mechanism of β-cell death triggered by the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interferon (IFN)-γ. The combination of TNF-α + IFN-γ induced DP5, p53 up-regulated modulator of apoptosis (PUMA), and Bim expression in human islets and rodent β-cells. DP5 and PUMA inactivation by RNA interference partially protected against TNF-α + IFN-γ-induced β-cell apoptosis. DP5 knock-out mice had increased β-cell area, and isolated islets from these mice were resistant to cytokine exposure. Bim expression was transcriptionally regulated by STAT1, and its activation triggered cleavage of caspases. Silencing of Bim protected rodent and human β-cells to a large extent against TNF-α + IFN-γ, indicating a major role of this BH3-only activator protein in the mechanism of apoptosis. Our data support a highly regulated and context-dependent modulation of specific Bcl-2 members controlling the mitochondrial pathway of β-cell apoptosis during insulitis.
authors.affiliation: Laboratory of Experimental Medicine, Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium.
authors.forename: Jenny
authors.initials: J
authors.lastname: Barthson
authors.forename: Carla M
authors.initials: CM
authors.lastname: Germano
authors.forename: Fabrice
authors.initials: F
authors.lastname: Moore
authors.forename: Adriano
authors.initials: A
authors.lastname: Maida
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Piero
authors.initials: P
authors.lastname: Marchetti
authors.forename: Conny
authors.initials: C
authors.lastname: Gysemans
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nuñez
authors.forename: Andrea
authors.initials: A
authors.lastname: Jurisicova
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Gurzov
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020868:Gene Silencing; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C484586:HRK protein, human; C107631:Hrk protein, mouse; D008565:Membrane Proteins; D009479:Neuropeptides; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; C495901:TP53 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma