Cytokine-Induced Inhibition of Insulin Release from Mouse Pancreatic β-Cells Deficient in Inducible Nitric Oxide Synthase

Andersson, Annika; Flodström, Malin; Sandler, Stellan

doi:10.1006/bbrc.2001.4361

Cited by 74 publications

(41 citation statements)

References 51 publications

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“…To investigate these issues in more detail, GLUTag and MIN6, a-TC1 cells, were used to examine cellular responses and expression of genes determining susceptibility to such cytotoxic insults. Individual cytokines (IL1b, IFNg, TNFa) and streptozotocin decreased cell viability in all three cell lines in a dose-dependent fashion, an effect which has been documented previously in b-cells (Gao et al 2000, Andersson et al 2001, Eizirik et al 2003, Kharroubi et al 2004, Zhang et al 2007). The LD 50 values for these agents were not significantly different for MIN6 and GLUTag cells, but they were 1.3-to 3.2-fold greater in a-TC1 cells exposed to streptozotocin, IL1b or TNFa.…”

Section: Discussionsupporting

confidence: 81%

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: 81%

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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“…Our data do suggest that NF B (p50) may potentiate induction of NOS in islets of Langerhans, as NO formation was less in cytokine-treated p50-deficient mouse islets than in wildtype islets. This reduction in NO formation had no effect on the degree of inhibition of insulin secretion observed after cytokine treatment of p50-deficient islets -an effect which may be partly due to a recently reported NOindependent pathway of cytokine-mediated inhibition of insulin secretion (Andersson et al 2001).…”

Section: Discussionmentioning

confidence: 52%

NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

Mabley¹,

Haskó²,

Liaudet³

et al. 2002

Journal of Endocrinology

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Insulin-dependent diabetes mellitus (IDDM) is a disease characterized by the autoimmune destruction of the pancreatic -cells, which requires the expression of a number of immune-related genes including major histocompatibility complex proteins, cytokines, chemokines, and cytotoxic enzymes, many of which are regulated by the transcription factor, NF B. Inhibition of the entire NF B family of transcription factors may be harmful, as these factors are involved in many normal physiological processes. However, identifying and targeting specific NF B subunits critical for the pathogenesis of disease may prove to be valuable in designing new therapeutic strategies. To assess the potential role of the NF B subunit, p50, in the development of IDDM, mice with gene disruption for NF B (p50) were investigated for susceptibility to IDDM. We found that p50-deficient mice were fully resistant against multiple low-dose streptozotocin-induced diabetes, a model of diabetes with a strong autoimmune component. The site of involvement of NF B (p50) lies at an early, critical juncture of immune activation and proinflammatory mediator production, because: (1) isolated islets of Langerhans from NF B (p50)-deficient mice were not protected from the islet dysfunction induced by in vitro application of proinflammatory cytokines; (2) p50-deficient mice were not resistant to diabetes induced by a single high dose of streptozotocin, a model with a large oxidant component and no autoimmune involvement; and (3) diabetes induced up-regulation of nitric oxide and interleukin-12 was blocked in the p50-deficient mice. Our data suggest that NF B (p50) has an essential role in the development of autoimmune diabetes. Selective therapeutic blockade of this subunit may be beneficial in preventing IDDM.

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“…In rodent beta cells, IL-1β alone or in combination with IFNγ induces the expression of inducible nitric oxide (NO) synthase (iNOS) resulting in production of NO. Using either pharmacological blockers of NO production or taking advantage of isolated islets from iNOS-deficient mice, several in vitro studies have shown that NO is a contributing factor in cytokine-induced impairment of beta cell secretory function and cell death [2][3][4][5][6][7]. Also, iNOSdeficient mice are significantly protected against chemically induced diabetes [7], further indicating that NO plays a role in the beta cell demise in type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt

et al. 2005

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Aims/hypothesis: Pro-inflammatory cytokines cause beta cell secretory dysfunction and apoptosis-a process implicated in the pathogenesis of type 1 diabetes. Cytokines induce the expression of inducible nitric oxide (NO) synthase (iNOS) leading to NO production. NO contributes to cytokine-induced apoptosis, but the underlying mechanisms are unclear. The aim of this study was to investigate whether NO modulates signalling via mitogenactivated protein kinases (MAPKs) and Akt. Materials and methods: MAPK activities in INS-1 cells and isolated islets were determined by immunoblotting and in vitro kinase assay. Apoptosis was determined by ELISA measurement of histone-DNA complexes present in cytoplasm. Results: Apoptosis in INS-1 cells induced by IL-1β plus IFNγ was dependent on NO production as demonstrated by the use of the NOS blocker N G -methyl-Larginine. Accordingly, an NO donor (S-nitroso-N-acetyl-D, L-penicillamine, SNAP) dose-dependently caused apoptosis in INS-1 cells. SNAP activated c-Jun N-terminal kinase (JNK) and p38 MAPK, but suppressed the activity of extracellular signal-regulated kinase MAPK. In rat islets, NOS inhibition decreased JNK and p38 activities induced by a 6-h exposure to IL-1β. Likewise, IL-1β-induced JNK and p38 activities were lower in iNOS (−/−) mouse islets than in wild-type islets. In human islets, SNAP potentiated IL-1β-induced JNK activation. The constitutive level of active, Ser473-phosphorylated Akt in INS-1 cells was suppressed by SNAP. IGF-I activated Akt and protected against SNAP-induced apoptosis. The anti-apoptotic effect of IGF-I was not associated with reduced JNK activation. Conclusions/interpretation: We suggest that NO contributes to cytokine-induced apoptosis via potentiation of JNK activity and suppression of Akt.

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Cytokine-Induced Inhibition of Insulin Release from Mouse Pancreatic β-Cells Deficient in Inducible Nitric Oxide Synthase

Cited by 74 publications

References 51 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

NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt

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