1. Cytokines tumor necrosis factor-α and interferon-γ induce pancreatic β-cell apoptosis through STAT1-mediated Bim protein activation.
- Author
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Barthson J, Germano CM, Moore F, Maida A, Drucker DJ, Marchetti P, Gysemans C, Mathieu C, Nuñez G, Jurisicova A, Eizirik DL, and Gurzov EN
- Subjects
- Adult, Aged, Animals, Antiviral Agents metabolism, Antiviral Agents pharmacology, Apoptosis drug effects, Apoptosis Regulatory Proteins genetics, Bcl-2-Like Protein 11, Cells, Cultured, Female, Gene Expression Regulation drug effects, Gene Expression Regulation physiology, Gene Silencing, Humans, Interferon-gamma genetics, Interferon-gamma pharmacology, Male, Membrane Proteins genetics, Mice, Mice, Knockout, Middle Aged, Neuropeptides genetics, Neuropeptides metabolism, Proto-Oncogene Proteins genetics, STAT1 Transcription Factor genetics, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha pharmacology, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Apoptosis physiology, Apoptosis Regulatory Proteins metabolism, Insulin-Secreting Cells metabolism, Interferon-gamma metabolism, Membrane Proteins metabolism, Proto-Oncogene Proteins metabolism, STAT1 Transcription Factor metabolism, Tumor Necrosis Factor-alpha metabolism
- 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.
- Published
- 2011
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