Dataset Information

Cytokines tumor necrosis factor-? and interferon-? induce pancreatic ?-cell apoptosis through STAT1-mediated Bim protein activation.

ABSTRACT: Type 1 diabetes is characterized by local inflammation (insulitis) in the pancreatic islets causing ?-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 ?-cell death triggered by the pro-inflammatory cytokines tumor necrosis factor (TNF)-? and interferon (IFN)-?. The combination of TNF-? + IFN-? induced DP5, p53 up-regulated modulator of apoptosis (PUMA), and Bim expression in human islets and rodent ?-cells. DP5 and PUMA inactivation by RNA interference partially protected against TNF-? + IFN-?-induced ?-cell apoptosis. DP5 knock-out mice had increased ?-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 ?-cells to a large extent against TNF-? + IFN-?, 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 ?-cell apoptosis during insulitis.

SUBMITTER: Barthson J

PROVIDER: S-EPMC3234786 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cytokines tumor necrosis factor-α and interferon-γ induce pancreatic β-cell apoptosis through STAT1-mediated Bim protein activation.

Barthson Jenny J Germano Carla M CM Moore Fabrice F Maida Adriano A Drucker Daniel J DJ Marchetti Piero P Gysemans Conny C Mathieu Chantal C Nuñez Gabriel G Jurisicova Andrea A Eizirik Decio L DL Gurzov Esteban N EN

The Journal of biological chemistry 20110921 45

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 islet ...[more]

PMID: 21937453

Similar Datasets

Project description:BackgroundIn humans, interferon-α treatment for chronic viral hepatitis is a well-recognized clinical model for inflammation-induced depression, but the molecular mechanisms underlying these effects are not clear. Following peripheral administration in rodents, interferon-α induces signal transducer and activator of transcription-1 (STAT1) within the hippocampus and disrupts hippocampal neurogenesis.MethodsWe used the human hippocampal progenitor cell line HPC0A07/03C to evaluate the effects of 2 concentrations of interferon-α, similar to those observed in human serum during its therapeutic use (500 pg/mL and 5000 pg/mL), on neurogenesis and apoptosis.ResultsBoth concentrations of interferon-α decreased hippocampal neurogenesis, with the high concentration also increasing apoptosis. Moreover, interferon-α increased the expression of interferon-stimulated gene 15 (ISG15), ubiquitin-specific peptidase 18 (USP18), and interleukin-6 (IL-6) via activation of STAT1. Like interferon-α, co-treatment with a combination of ISG15, USP18, and IL-6 was able to reduce neurogenesis and enhance apoptosis via further downstream activation of STAT1. Further experiments showed that ISG15 and USP18 mediated the interferon-α-induced reduction in neurogenesis (potentially through upregulation of the ISGylation-related proteins UBA7, UBE2L6, and HERC5), while IL-6 mediated the interferon-α-induced increase in apoptosis (potentially through downregulation of aquaporin 4). Using transcriptomic analyses, we showed that interferon-α regulated pathways involved in oxidative stress and immune response (e.g., Nuclear Factor (erythroid-derived 2)-like 2 [Nrf2] and interferon regulatory factor [IRF] signaling pathway), neuronal formation (e.g., CAMP response element-binding protein [CREB] signaling), and cell death regulation (e.g., tumor protein(p)53 signaling).ConclusionsWe identify novel molecular mechanisms mediating the effects of interferon-α on the human hippocampus potentially involved in inflammation-induced neuropsychiatric symptoms.

Dataset Information

Cytokines tumor necrosis factor-? and interferon-? induce pancreatic ?-cell apoptosis through STAT1-mediated Bim protein activation.

Publications

Cytokines tumor necrosis factor-α and interferon-γ induce pancreatic β-cell apoptosis through STAT1-mediated Bim protein activation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets