Cytokines Tumor Necrosis Factor-α and Interferon-γ Induce Pancreatic β-Cell Apoptosis through STAT1-mediated Bim Protein Activation
Copyright policy )Cytokines Tumor Necrosis Factor-α and Interferon-γ Induce Pancreatic β-Cell Apoptosis through STAT1-mediated Bim Protein Activation
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.
- KU Leuven Belgium
- University of Michigan–Flint United States
- University of Michigan–Ann Arbor United States
- Université Libre de Bruxelles Belgium
- University of Pisa Italy
Adult, Male, Cells, Knockout, STAT1 Transcription Factor -- genetics -- metabolism, Apoptosis Regulatory Proteins -- genetics -- metabolism, Apoptosis, Antiviral Agents -- metabolism -- pharmacology, Antiviral Agents, Tumor Suppressor Protein p53 -- genetics -- metabolism, Interferon-gamma, Mice, Proto-Oncogene Proteins -- genetics -- metabolism, Gene Expression Regulation -- drug effects -- physiology, Insulin-Secreting Cells, Animals, Humans, Gene Silencing, Cells, Cultured, Aged, Mice, Knockout, Cultured, Bcl-2-Like Protein 11, Neuropeptides, Membrane Proteins, Sciences bio-médicales et agricoles, Middle Aged, Apoptosis -- drug effects -- physiology, Interferon-gamma -- genetics -- metabolism -- pharmacology, Gene Expression Regulation, Insulin-Secreting Cells -- metabolism, Membrane Proteins -- genetics -- metabolism, Neuropeptides -- genetics -- metabolism, Female, Apoptosis Regulatory Proteins, Tumor Necrosis Factor-alpha -- genetics -- metabolism -- pharmacology
Adult, Male, Cells, Knockout, STAT1 Transcription Factor -- genetics -- metabolism, Apoptosis Regulatory Proteins -- genetics -- metabolism, Apoptosis, Antiviral Agents -- metabolism -- pharmacology, Antiviral Agents, Tumor Suppressor Protein p53 -- genetics -- metabolism, Interferon-gamma, Mice, Proto-Oncogene Proteins -- genetics -- metabolism, Gene Expression Regulation -- drug effects -- physiology, Insulin-Secreting Cells, Animals, Humans, Gene Silencing, Cells, Cultured, Aged, Mice, Knockout, Cultured, Bcl-2-Like Protein 11, Neuropeptides, Membrane Proteins, Sciences bio-médicales et agricoles, Middle Aged, Apoptosis -- drug effects -- physiology, Interferon-gamma -- genetics -- metabolism -- pharmacology, Gene Expression Regulation, Insulin-Secreting Cells -- metabolism, Membrane Proteins -- genetics -- metabolism, Neuropeptides -- genetics -- metabolism, Female, Apoptosis Regulatory Proteins, Tumor Necrosis Factor-alpha -- genetics -- metabolism -- pharmacology
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