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Title: Cytokines tumor necrosis factor-{alpha} and interferon-{gamma} induce pancreatic {beta}-cell apoptosis through STAT1-mediated Bim protein activation
Authors: Barthson, Jenny ×
Germano, Carla M
Moore, Fabrice
Maida, Adriano
Drucker, Daniel J
Marchetti, Piero
Gysemans, Conny
Mathieu, Chantal
Nunez, Gabriel
Jurisicova, Andrea
Eizirik, Decio L
Gurzov, Esteban N #
Issue Date: Nov-2011
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Journal of Biological Chemistry vol:286 issue:45 pages:39632-39643
Abstract: Type 1 diabetes is characterized by local inflammation (insulitis) in the pancreatic islets causing β-cell loss. The mitochondrial p athway 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, 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 knockout 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.
URI: 
ISSN: 0021-9258
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
× corresponding author
# (joint) last author

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