Cytokine-induced apoptosis and necrosis are preceded by disruption of the mitochondrial membrane potential (Δψm) in pancreatic RINm5F cells: prevention by Bcl-2

Barbu, Andreea; Welsh, Nils; Saldeen, Johan

doi:10.1016/s0303-7207(02)00009-6

Cited by 116 publications

(88 citation statements)

References 41 publications

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“…Bcl-2 protein was only detected weakly in pancreata of FTS-administered group by Western blotting at 24 hr after LPS injection (data not shown). The combination of IL-1β, TNF-α and interferon-γ presently induced disruption of the mitochondrial membrane potential in rat insulin-producing RINm5F cells and overexpression of the antiapoptotic protein Bcl-2 increased the mitochondrial membrane potential, which was paralleled by protection against cytokine-induced apoptosis and necrosis (6,14,17,18,35,39,47).…”

Section: Discussionmentioning

confidence: 95%

Serum Thymic Factor Prevents LPS‐Induced Pancreatic Cell Damage in Mice via Up‐Regulation of Bcl‐2 Expression in Pancreas

Saitoh

Awaya

Sakudo

et al. 2004

Microbiology and Immunology

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The protective effect of synthetic serum thymic factor (FTS) nonapeptide on lipopolysaccharide (LPS)‐induced pancreatic cell damage in 10‐week‐old BALB/c male mice was investigated. Mice were divided into three groups. Group I was treated with LPS (10 μg/head; i.p.) (LPS‐treated mice). Group II was administered with FTS (50 μg/head; i.p.) 24 hr before treatment with LPS and complemented immediately before LPS injection with FTS (50 μg/head; i.p.) (FTS‐administered mice). Group III was only treated with the same volume of saline (control mice). Treatment of LPS in vivo resulted in the destruction of pancreatic acinar cells. In those cells, many apoptotic cells were detected by immunohistochemistry using an anti‐single stranded DNA antibody. Immunohistochemistry and reverse transcription‐polymerase chain reaction (RT‐PCR) revealed that LPS treatment also caused low or a lack of insulin expression in pancreatic islets. In contrast, morphological change was not seen and apoptotic cell death was suppressed in pancreatic cells of FTS‐administered mice. Moreover, insulin expression was normal in those mice. FTS administration enhanced expression of Bcl‐2 mRNA levels in pancreatic tissues and IL‐6 mRNA levels in splenocytes significantly compared with those of LPS treatment at 3 hr after LPS injection. These findings suggest that FTS prevents LPS‐induced cell damage via enhancing Bcl‐2 expression in the pancreas and systemic IL‐6 production.

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Section: Discussionmentioning

confidence: 95%

Serum Thymic Factor Prevents LPS‐Induced Pancreatic Cell Damage in Mice via Up‐Regulation of Bcl‐2 Expression in Pancreas

Saitoh

Awaya

Sakudo

et al. 2004

Microbiology and Immunology

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“…Thus, because of the predominantly potential-dependent mechanism of ROS formation in ␤-cell mitochondria, development of Ca 2ϩ -phosphateinduced MPT does not involve increased mitochondrial ROS production. However, it is likely that increased ROS stimulated by additional factors (high glucose, fatty acids, and ceramides) (62) or formed exogenously (pancreatic macrophages) (14) can significantly contribute to MPT opening in ␤-cells.…”

Section: Fig 2 Effect Of Ca 2؉ On Mitochondrial Function (Respiratimentioning

confidence: 99%

“…Studies examining the role of cytokines in the pancreatic ␤-cell indicated, by means of mitochondrial depolarization and cytochrome c release, that MPT is a common effector of both apoptosis and necrosis (14,15). Thus, MPT is implicated in ␤-cell death, which is a key factor in the etiology of type 1 diabetes and a potentially important contributor to some forms of type 2 diabetes (16).…”

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confidence: 99%

The Characterization of Mitochondrial Permeability Transition in Clonal Pancreatic β-Cells

Koshkin

Bikopoulos

Chan

et al. 2004

Journal of Biological Chemistry

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Mitochondrial permeability transition (MPT), which contributes substantially to the regulation of normal mitochondrial metabolism, also plays a crucial role in the initiation of cell death. It is known that MPT is regulated in a tissue-specific manner. The importance of MPT in the pancreatic ␤-cell is heightened by the fact that mitochondrial bioenergetics serve as the main glucose-sensing regulator and energy source for insulin secretion. In the present study, using MIN6 and INS-1 ␤-cells, we revealed that both Ca 2؉ -phosphate-and oxidant-induced MPT is remarkably different from other tissues. Ca 2؉ -phosphate-induced transition is accompanied by a decline in mitochondrial reactive oxygen species production related to a significant potential dependence of reactive oxygen species formation in ␤-cell mitochondria. Hydroperoxides, which are indirect MPT co-inducers active in liver and heart mitochondria, are inefficient in ␤-cell mitochondria, due to the low mitochondrial ability to metabolize them. Direct cross-linking of mitochondrial thiols in pancreatic ␤-cells induces the opening of a low conductance ion permeability of the mitochondrial membrane instead of the full scale MPT opening typical for liver mitochondria. Low conductance MPT is independent of both endogenous and exogenous Ca 2؉ , suggesting a novel type of nonclassical MPT in ␤-cells. It results in the conversion of electrical transmembrane potential into ⌬pH instead of a decrease in total protonmotive force, thus mitochondrial respiration remains in a controlled state. Both Ca 2؉ -and oxidant-induced MPTs are phosphate-dependent and, through the "phosphate flush" (associated with stimulation of insulin secretion), are expected to participate in the regulation in ␤-cell glucose-sensing and secretory activity.Mitochondrial permeability transition (MPT) 1 is a permeability increase of the inner mitochondrial membrane to solutes of molecular mass up to ϳ1500 Da, which is caused by an opening of specific nonselective proteinaceous pores in the inner mitochondrial membrane (1, 2). Increased permeability of the inner membrane is initiated by an increased level of intramitochondrial Ca 2ϩ and is regulated by multiple effectors, including inorganic phosphate, the redox state of pyridine nucleotides and thiols (oxidative stress), membrane potential, cyclosporin A, and other factors (3). MPT pores are thought to have at least two open conformations and a variable degree of reversibility. Most importantly, MPT in its different forms contributes to both normal cell physiology (regulation of oxidative phosphorylation and Ca 2ϩ metabolism) and to regulatory processes leading to apoptosis (2-4). Specific features of MPT show significant tissue-specific variability (5-8). The most significant and well documented deviation from classical MPT described in liver mitochondria was observed in brain tissue (9). Brain mitochondria demonstrate high resistance to MPT opening (10), low sensitivity to cyclosporin A (5), different responses to MPT modifiers, and a distinctive...

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“…[1][2][3][4][5] NO is one of the mediators of cellular responses induced by cytokines. 4,6 Several cytokines, including mixed cocktail of cytokines, interleukin-1β (IL-1β), interferon γ, tumor necrosis factor α, IL-17 7 and IL-6, 8 increase the production of NO because they induce iNOS expression.…”

Section: Introductionmentioning

confidence: 99%

Regulation of pancreatic β-cell survival by nitric oxide

Bedoya¹,

Salguero-Aranda

Cahuana

et al. 2012

Islets

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Cytokine-induced apoptosis and necrosis are preceded by disruption of the mitochondrial membrane potential (Δψm) in pancreatic RINm5F cells: prevention by Bcl-2

Cited by 116 publications

References 41 publications

Serum Thymic Factor Prevents LPS‐Induced Pancreatic Cell Damage in Mice via Up‐Regulation of Bcl‐2 Expression in Pancreas

Serum Thymic Factor Prevents LPS‐Induced Pancreatic Cell Damage in Mice via Up‐Regulation of Bcl‐2 Expression in Pancreas

The Characterization of Mitochondrial Permeability Transition in Clonal Pancreatic β-Cells

Regulation of pancreatic β-cell survival by nitric oxide

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