Cytokines and nitric oxide inhibit the enzyme activity of catalase but not its protein or mRNA expression in insulin-producing cells

Sigfrid, Louise; Cunningham, James M.; Beeharry, Neil; Lortz, Stephan; Tiedge, Markus; Lenzen, Sigurd; Carlsson, Carina; Green, I C

doi:10.1677/jme.0.0310509

Cited by 60 publications

(35 citation statements)

References 52 publications

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“…Cytokine cocktail increased Nfkb1 transcription in all cell lines, which was accompanied by strong induction of Nos2 expression and a significant increase in nitrite levels in the culture medium as observed previously in cytokine-exposed b-cell models, human islets and FACSpurified rat b-cells (Corbett et al 1993, Lortz et al 2000, Lakey et al 2001, Sigfrid et al 2003, Souza et al 2004, Larsen et al 2007, Zhang et al 2007, Gurzov et al 2008, Moore et al 2011, 2012. Although gene expression data does not reflect activity of NFkB, it should be noted that NFkB autoregulates its own expression.…”

Section: Discussionsupporting

confidence: 66%

Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells

Vasu

Moffett

McClenaghan

et al. 2014

Journal of Molecular Endocrinology

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Little is known about responses of intestinal L-cells to chemical or cytokine-mediated attack and how these compare with pancreatic b-or a-cells. Administration of streptozotocin to mice induced severe diabetes, islet lymphocytic infiltration, increased a-cell proliferation and decreased numbers of b-and L-cells. In vitro, streptozotocin and cytokines reduced cell viability with higher lethal dose 50 values for a-TC1 cells. mRNA expression of Glut2 was lower and Cat was greater in GLUTag and a-TC1 cells compared with MIN6 cells. Cytotoxins affected the transcription of genes involved in secretion in GLUTag and MIN6 cells. They are also involved in upregulation of antioxidant defence enzymes, transcription of NfkB and Nos2, and production of nitrite in all cell types. Cytotoxin-induced DNA damage and apoptosis were apparent in all cells, but a-TC1 cells were less severely affected. Thus, responses of GLP1-secreting L-cells to cytotoxicity resemble b-cells, whereas a-cells are resistant due to differences in the expression of genes involved in cytotoxicity or antioxidant defence.

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Section: Discussionsupporting

confidence: 66%

Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells

Vasu

Moffett

McClenaghan

et al. 2014

Journal of Molecular Endocrinology

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“…IL-1␤ toxicity is enhanced in the presence of TNF-␣ and IFN-␥ probably by a signaling pathways cross talk between these cytokines (46 -48). In addition, the induction of iNOS and the subsequent production of NO through cytokines is able to reduce catalase enzyme activity by binding to the iron of the catalase haem groups (49). Although the mitochondrial localization of catalase could theoretically decrease this inactivation reaction, this was not the case.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Catalase Overexpression Protects Insulin-Producing Cells Against Toxicity of Reactive Oxygen Species and Proinflammatory Cytokines

et al. 2004

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Insulin-producing cells are known for their extremely low antioxidant equipment with hydrogen peroxide (H 2 O 2 )-inactivating enzymes. Therefore, catalase was stably overexpressed in mitochondria and for comparison in the cytoplasmic compartment of insulin-producing RINm5F cells and analyzed for its protective effect against toxicity of reactive oxygen species (ROS) and proinflammatory cytokines. Only mitochondrial overexpression of catalase provided protection against menadione toxicity, a chemical agent that preferentially generates superoxide radicals intramitochondrially. On the other hand, the cytoplasmic catalase overexpression provided better protection against H 2 O 2 toxicity. Mitochondrial catalase overexpression also preferentially protected against the toxicity of interleukin-1␤ (IL-1␤) and a proinflammatory cytokine mixture (IL-1␤, tumor necrosis factor-␣ [TNF-␣], and ␥-interferon [IFN-␥])that is more toxic than IL-1␤ alone. Thus, it can be concluded that targeted overexpression of catalase in the mitochondria provides particularly effective protection against cell death in all situations in which ROS are generated intramitochondrially. The observed higher rate of cell death after exposure to a cytokine mixture in comparison with the weaker effect of IL-1␤ alone may be due to an additive toxicity of TNF-␣ through ROS formation in mitochondria. The results emphasize the central role of mitochondrially generated ROS in the cytokine-mediated cell destruction of insulin-producing cells.

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“…3) [36,37] as well as in other cell types [38,39] and the inhibition of catalase enzyme activity by NO [40], which fosters H 2 O 2 generation. IL-1β is also known to decrease glutathione synthase expression in rat islets, and therefore additionally reduces antioxidative capacity of islets [41].…”

Section: Discussionmentioning

confidence: 99%

Importance of mitochondrial superoxide dismutase expression in insulin-producing cells for the toxicity of reactive oxygen species and proinflammatory cytokines

et al. 2005

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Aims/hypothesis: Free radicals generated in mitochondria play a crucial role in the toxic effects of cytokines upon insulin-producing cells. This study therefore investigated the role of manganese superoxide dismutase (MnSOD) in cytokine-mediated toxicity in insulin-producing cells. Methods: MnSOD was either stably overexpressed (MnSODsense) or stably suppressed (MnSODantisense) in insulin-producing RINm5F cells. Cell viability was quantified after incubation with different chemical reactive oxygen species (ROS) generators and with cytokines (IL-1β alone or a mixture of IL-1β, TNF-α and IFN-γ). Additionally, cell proliferation and endogenous MnSOD protein expression were determined after exposure to cytokines. Results: After incubation with hydrogen peroxide (H 2 O 2 ) or hypoxanthine/xanthine oxidase no significant differences were observed in viability between control and MnSOD sense or MnSODantisense clones. MnSOD overexpression reduced the viability of MnSODsense cells after exposure to the intracellular ROS generator menadione compared with control and MnSODantisense cells. MnSODsense cells also showed the highest susceptibility to cytokine toxicity with more than 75% loss of viability and a significant reduction of the proliferation rate after 72 h of incubation with a cytokine mixture. In comparison with control cells (67% viability loss), the reduction of viability in MnSODantisense cells was lower (50%), indicating a sensitising role of MnSOD in the progression of cytokine toxicity. The cell proliferation rate decreased in parallel to the reduction of cell viability. The MnSOD expression level after exposure to cytokines was also significantly lower in Mn SODantisense cells than in control or MnSODsense cells. Conclusions/interpretation: The increase of the mitochondrial imbalance between the superoxide-and the H 2 O 2 -inactivating enzyme activities corresponds with a greater susceptibility to cytokines. Thus optimal antioxidative strategies to protect insulin-producing cells against cytokine toxicity may comprise a combined overexpression of H 2 O 2 -inactivating enzymes or suppression of MnSOD activity.

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Cytokines and nitric oxide inhibit the enzyme activity of catalase but not its protein or mRNA expression in insulin-producing cells

Cited by 60 publications

References 52 publications

Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells

Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells

Mitochondrial Catalase Overexpression Protects Insulin-Producing Cells Against Toxicity of Reactive Oxygen Species and Proinflammatory Cytokines

Importance of mitochondrial superoxide dismutase expression in insulin-producing cells for the toxicity of reactive oxygen species and proinflammatory cytokines

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