The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells

Eizirik, Décio L.; Flodström, Malin; Karlsen, Allan E.; Welsh, Nils

doi:10.1007/bf00403906

Cited by 279 publications

(130 citation statements)

References 162 publications

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“…One of the mechanisms by which cytokine-induced NF-B activation can impair beta-cell functions and, in part, mediate beta-cell death is via induction of the expression of the inducible form of nitric oxide synthase and subsequent NO production (12,13,26,27). We measured NO formation as nitrite accumulation in the culture media of islets isolated from Dox-treated or untreated mice and incubated for 48 h in the presence or absence of IL-1␤ and INF-␥ (with or without Dox).…”

Section: Inhibition Of Cytokine-induced Nf-b Nuclear Translocation Inmentioning

confidence: 99%

Conditional and specific NF-κB blockade protects pancreatic beta cells from diabetogenic agents

Eldor¹,

Yeffet²,

Baum³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Type 1 diabetes is characterized by the infiltration of inflammatory cells into pancreatic islets of Langerhans, followed by the selective and progressive destruction of insulin-secreting beta cells. Isletinfiltrating leukocytes secrete cytokines such as IL-1␤ and IFN-␥, which contribute to beta cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-B is an important component of the signal triggering beta cell apoptosis. To study the in vivo role of NF-B in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-B protein inhibitor (⌬NI B␣), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro, islets expressing the ⌬NI B␣ protein were resistant to the deleterious effects of IL-1␤ and IFN-␥, as assessed by reduced NO production and beta-cell apoptosis. This effect was even more striking in vivo, where nearly complete protection against multiple low-dose streptozocin-induced diabetes was observed, with reduced intraislet lymphocytic infiltration. Our results show in vivo that beta cell-specific activation of NF-B is a key event in the progressive loss of beta cells in diabetes. Inhibition of this process could be a potential effective strategy for beta-cell protection.apoptosis ͉ cytokine ͉ diabetes ͉ transgenic mice ͉ insulin

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Section: Inhibition Of Cytokine-induced Nf-b Nuclear Translocation Inmentioning

confidence: 99%

Conditional and specific NF-κB blockade protects pancreatic beta cells from diabetogenic agents

Eldor¹,

Yeffet²,

Baum³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

234

211

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“…is known to stimulate NO production in islet ␤-cells via induction of iNOS, and NO production has been implicated in IL-1␤-mediated ␤-cell destruction (2)(3)(4)(5)21). In previous studies, we have shown that the iNOS inhibitor, N G -monomethyl-L-arginine can block cytotoxicity mediated by IL-1␤ and that INS-1 res cells do not produce NO in response to acute treatment with IFN-␥, IL-1␤, or IL-1␤ plus IFN-␥ (14, 21).…”

Section: Adenovirus-mediated Overexpression Of Stat-1␣ Reduces No Promentioning

confidence: 99%

“…Destruction of ␤-cells appears to result from direct contact with infiltrating T-cells and macrophages and exposure to inflammatory cytokines such as IFN-␥, 1 IL-1␤, and TNF-␣ that such cells produce (1)(2)(3)(4)(5). Insulin replacement by injection, the current treatment, fails to replicate the precise control of fuel homeostasis afforded by normal regulation of insulin secretion in response to glucose and other physiological cues.…”

mentioning

confidence: 99%

Expression of the Transcription Factor STAT-1α in Insulinoma Cells Protects against Cytotoxic Effects of Multiple Cytokines

Chen¹,

Hohmeier²,

Newgard³

2001

Journal of Biological Chemistry

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Destruction of pancreatic islet ␤-cells in type 1 diabetes appears to result from direct contact with infiltrating T-cells and macrophages and exposure to inflammatory cytokines such as interferon (IFN)-␥, interleukin (IL)-Type 1 diabetes is caused by autoimmune destruction of pancreatic islet ␤-cells. Destruction of ␤-cells appears to result from direct contact with infiltrating T-cells and macrophages and exposure to inflammatory cytokines such as IFN-␥, 1 IL-1␤, and TNF-␣ that such cells produce (1-5). Insulin replacement by injection, the current treatment, fails to replicate the precise control of fuel homeostasis afforded by normal regulation of insulin secretion in response to glucose and other physiological cues. Islet transplantation has therefore been investigated as an alternative to insulin injection therapy for more than 3 decades (6, 7). Success in this area had been very limited until a recent trial in Edmonton, Alberta, Canada, in which a combination of mild immunosuppressive agents were used in conjunction with freshly isolated islet tissue to achieve insulin independence in seven successive patients studied for up to 14.9 months post-transplant (8).Unfortunately, enthusiasm for this important finding is tempered by the fact that the number of human pancreata available for islet transplantation in the United States is on the order of several thousand per year (6, 7), which does not approach the number of patients that could benefit from this new form of therapy. To deal with this problem, we and others have been attempting to develop a replenishable source of cells that could serve as islet surrogates for cell-based insulin replacement in diabetes (9 -13). One working concept is that immortalized cell lines engineered for robust glucose-stimulated insulin secretion can be transplanted in the context of a cellimpermeant macroencapsulation device, preventing contact of cellular elements of the immune system with the transplanted cells (11). However, because such devices are envisioned to allow rapid exit of insulin, as well as highly efficient equilibration of nutrients, oxygen, and waste products, it is anticipated that soluble mediators of immunological damage such as cytokines or reactive oxygen species will readily gain access to the cells within the device. Thus, development of methods to protect transplanted cells against diffusable, noncellular mediators of immunological destruction may be important for the eventual success of cell-based insulin replacement strategies.Recently, we described a method for selection of cell lines with resistance to the cytotoxic effects of exposure to a mixture of IL-1␤ and IFN-␥, known mediators of ␤-cell destruction in type 1 diabetes (14). This involved growth of INS-1 insulinoma cells in progressively elevated concentrations of the two cytokines over an 8-week period and selection of surviving cells. The resultant cell line, termed INS-1 res , was 80% viable after 5 days of exposure to the combination of 10 ng/ml IL-1␤ and 100 units/ml IFN-␥, while less th...

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“…Cytokines such as IL-1 (rat) and a combination of IL-1 ϩ IFN-␥ (mouse and human) stimulate the expression of the inducible isoform of nitric-oxide synthase (NOS) and the production of micromolar levels of nitric oxide by ␤-cells (1)(2)(3)(4). Nitric oxide attenuates insulin secretion by inhibiting the oxidation of glucose to CO 2 and the activity of mitochondrial iron-sulfur center containing enzymes such as aconitase and complexes of the electron transport system (5,6).…”

mentioning

confidence: 99%

FoxO1 and SIRT1 Regulate β-Cell Responses to Nitric Oxide

Hughes

Meares

Hansen

et al. 2011

Journal of Biological Chemistry

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For many cell types, including pancreatic ␤-cells, nitric oxide is a mediator of cell death; paradoxically, nitric oxide can also activate pathways that promote the repair of cellular damage. In this report, a role for FoxO1-dependent transcriptional activation and its regulation by SIRT1 in determining the cellular response to nitric oxide is provided. In response to nitric oxide, FoxO1 translocates from the cytoplasm to the nucleus and stimulates the expression of the DNA repair gene GADD45␣, resulting in FoxO1-dependent DNA repair. FoxO1-dependent gene expression appears to be regulated by the NAD ؉ -dependent deacetylase SIRT1. In response to SIRT1 inhibitors, the FoxO1-dependent protective actions of nitric oxide (GADD45␣ expression and DNA repair) are attenuated, and FoxO1 activates a proapoptotic program that includes PUMA (p53-up-regulated mediator of apoptosis) mRNA accumulation and caspase-3 cleavage. These findings support primary roles for FoxO1 and SIRT1 in regulating the cellular responses of ␤-cells to nitric oxide.Nitric oxide plays a central role in regulating the response(s) of pancreatic ␤-cells to cytokine treatment. Cytokines such as IL-1 (rat) and a combination of IL-1 ϩ IFN-␥ (mouse and human) stimulate the expression of the inducible isoform of nitric-oxide synthase (NOS) and the production of micromolar levels of nitric oxide by ␤-cells (1-4). Nitric oxide attenuates insulin secretion by inhibiting the oxidation of glucose to CO 2 and the activity of mitochondrial iron-sulfur center containing enzymes such as aconitase and complexes of the electron transport system (5, 6). The result is a 4-fold reduction in cellular ATP concentration (2, 7) that leads to the inhibition of glucose-induced insulin secretion due to the inability to generate sufficient levels of ATP to close the ATPsensitive K ϩ channels, an event required for ␤-cell depolarization and Ca 2ϩ -dependent exocytosis (8, 9). In addition to the inhibition of ␤-cell function, nitric oxide induces DNA strand breaks and oxidative DNA damage (10, 11).The inhibitory actions of IL-1 on ␤-cell function and DNA damage are reversible (12, 13). The addition of a NOS inhibitor to islets pretreated for 24 h with IL-1 (without removing IL-1) results in a time-dependent recovery of insulin secretion and mitochondrial function (3) and the repair of damaged DNA (14,15). This recovery response requires new gene expression, the activation of JNK, and can be stimulated by nitric oxide (16,17). The ability of ␤-cells to recover from cytokine-and nitric oxide-induced damage is temporally limited. Following a 36-h exposure to IL-1, ␤-cells are no longer capable of recovering metabolic and secretory function, and the islets are committed to death (14, 18). Studies have shown that cytokines can kill ␤-cells by nitric oxide-dependent and -independent necrotic and apoptotic mechanisms (19 -26). This dichotomy in the type of cell death that has been observed appears to reflect the temporal changes in the metabolic responses and the extent of DNA damage ca...

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The harmony of the spheres: inducible nitric oxide synthase and related genes in pancreatic beta cells

Cited by 279 publications

References 162 publications

Conditional and specific NF-κB blockade protects pancreatic beta cells from diabetogenic agents

Conditional and specific NF-κB blockade protects pancreatic beta cells from diabetogenic agents

Expression of the Transcription Factor STAT-1α in Insulinoma Cells Protects against Cytotoxic Effects of Multiple Cytokines

FoxO1 and SIRT1 Regulate β-Cell Responses to Nitric Oxide

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