Tumor Necrosis Factor- -Activated Cell Death Pathways in NIT-1 Insulinoma Cells and Primary Pancreatic   Cells

Stephens, Leigh A.

doi:10.1210/en.140.7.3219

Cited by 57 publications

(57 citation statements)

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“…However, the in vivo role of the cytokine in diabetes development has not yet been fully elucidated. Its diabetogenic role was suggested in some studies (13)(14)(15)(16)(17)(18), whereas opposite effects were reported in other studies (19,20). Our IFN-␥/TNF-␣ synergism model nicely explains why transgenic expression of TNF-␣ alone could not induce diabetes in some of the previous studies in which pancreatic expression of TNF-␣ alone did not accelerate diabetes development (21).…”

Section: Discussionsupporting

confidence: 55%

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IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

Suk

Kim

et al. 2001

The Journal of Immunology

208

187

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Fas ligand (FasL), perforin, TNF-α, IL-1, and NO have been considered as effector molecule(s) leading to β cell death in autoimmune diabetes. However, the real culprit(s) in β cell destruction have long been elusive, despite intense investigation. We and others have demonstrated that FasL is not a major effector molecule in autoimmune diabetes, and previous inability to transfer diabetes to Fas-deficient nonobese diabetic (NOD)-lpr mice was due to constitutive FasL expression on lymphocytes from these mice. Here, we identified IFN-γ/TNF-α synergism as the final effector molecules in autoimmune diabetes of NOD mice. A combination of IFN-γ and TNF-α, but neither cytokine alone, induced classical caspase-dependent apoptosis in insulinoma and pancreatic islet cells. IFN-γ treatment conferred susceptibility to TNF-α-induced apoptosis on otherwise resistant insulinoma cells by STAT1 activation followed by IFN regulatory factor (IRF)-1 induction. IRF-1 played a central role in IFN-γ/TNF-α-induced cytotoxicity because inhibition of IRF-1 induction by antisense oligonucleotides blocked IFN-γ/TNF-α-induced cytotoxicity, and transfection of IRF-1 rendered insulinoma cells susceptible to TNF-α-induced cytotoxicity. STAT1 and IRF-1 were expressed in pancreatic islets of diabetic NOD mice and colocalized with apoptotic cells. Moreover, anti-TNF-α Ab inhibited the development of diabetes after adoptive transfer. Taken together, our results indicate that IFN-γ/TNF-α synergism is responsible for autoimmune diabetes in vivo as well as β cell apoptosis in vitro and suggest a novel signal transduction in IFN-γ/TNF-α synergism that may have relevance in other autoimmune diseases and synergistic anti-tumor effects of the two cytokines.

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Section: Discussionsupporting

confidence: 55%

“…The role of TNF-␣ as an effector has been extremely ambiguous. Its diabetogenic role was suggested in some studies (13)(14)(15)(16)(17)(18), whereas opposite effects were reported in other studies (19,20). Neonatal islet-specific expression of TNF-␣ promoted diabetes by enhancing the presentation of islet Ags (16,17).…”

mentioning

confidence: 98%

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

Suk

Kim

et al. 2001

The Journal of Immunology

208

187

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“…34 It is of note that primary b pancreatic cells and insulinoma cells have been shown to express low levels of the p55 receptor but not the p75 receptor. 31 The potential cytotoxic effects of TNFa on HIT-T15 cells has not been examined in our study. This possibility seems unlikely, however, given that the cytotoxic effects of TNFa on b-cells apparently require higher concentrations of TNFa, 35 or the simultaneous presence of other cytokines such as IFN-g andaor IL-1b, 36 ± 38 which was not the case in our system.…”

Section: Inhibition Of Insulin Transcription By Tnfa and Leptinmentioning

confidence: 93%

“…6 ± 8 TNFa activity has been shown to exist in pancreatic islets and in insulinoma cells. 30,31 Thus, the mechanism of TNFa-mediated insulin resistance that exist in peripheral tissues, could also be expected to operate on pancreatic b-cells and in¯uence their function, as they also express insulin receptors that are required for normal glucose-stimulated insulin secretion. 5 Interestingly, it was demonstrated that insulin receptor signaling also appears to in¯uence insulin gene expression and insulin content in the b-cell.…”

Section: Inhibition Of Insulin Transcription By Tnfa and Leptinmentioning

confidence: 99%

TNFα and leptin inhibit basal and glucose-stimulated insulin secretion and gene transcription in the HIT-T15 pancreatic cells

Tsiotra¹,

Tsigos²,

Raptis

2001

Int J Obes

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BACKGROUND: Tumor necrosis factor a (TNFa), a cytokine produced at in¯ammatory sites and in adipose tissue, is known primarily for its detrimental effects on insulin action. There is evidence to suggest that TNFa may also in¯uence b-cell function. Leptin is another adipose tissue-derived hormone that might also act on b-cells. OBJECTIVE: We explored the independent and combined effects of TNFa and leptin upon basal and glucose-stimulated insulin transcription and secretion in the HIT-T15 pancreatic b cell line. METHODS: Cells were cultured for 40 h in the presence of near-normal basal (7 mM) or high (16.7 mM) glucose and treated with either TNFa (1, 10 and 50 ngaml) or leptin (10, 50 and 100 ngaml) or both together. Insulin concentrations were measured by radioimmunoassay. Insulin mRNA levels were evaluated by a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method, after normalization with b-actin mRNA. RESULTS: TNFa signi®cantly suppressed basal and glucose-stimulated insulin secretion and proinsulin mRNA transcription in a dose-dependent manner, an effect that was more powerful in the presence of high glucose. Leptin also inhibited dosedependent insulin mRNA and protein at both glucose concentrations, but did not appear to further potentiate the suppressive effects of TNFa. CONCLUSION: TNFa suppresses both basal and glucose-stimulated insulin transcription and secretion in HIT-T15 cells, an effect that is enhanced signi®cantly by high glucose. Leptin also independently inhibits basal and glucose-stimulated insulin secretion and transcription but does not modify TNFa effects. These effects might contribute to the abnormalities of glucose metabolism that characterize conditions of increased TNFa andaor leptin production.

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“…Defining the signalling components of apoptosis present in beta cells is important because it could provide insights into potential pathogenic mechanisms and might lead to the development of pharmacological interventions for the treatment of Type I diabetes. Several apoptosis signalling pathways, initiated by death receptor ligands such as Fas ligand (FasL) and TNF-α have been shown to be active in mouse islet beta cells and could be involved in destructive insulitis [4,5,6,7]. TRAIL (also known as Apo2 ligand) is a 40-kDa type II transmembrane protein that is structurally related to the TNF family of proteins including TNF-α and FasL [8,9].…”

mentioning

confidence: 99%

TNF-Related Apoptosis-Inducing Ligand Death Pathway-Mediated Human Beta-Cell Destruction

Metzger

Wang

et al. 2002

Diabetologia

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Aims/hypothesis. The aim of this study is to investigate whether apoptosis in human beta cells can be related to the induction of the tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) pathway. Methods. We examined the expression of TRAIL and TRAIL receptors in two human pancreatic beta-cell lines and in human primary islet cells using RT-PCR assays and flow cytometric analyses and tested TRAIL-mediated beta-cell destruction in 51 Cr release cytotoxicity assays, Annexin-V and APO-DIREC assays.Results. Most of the human beta cells express TRAIL receptors-R1, -R2, -R3, -R4 and/or TRAIL. TRAIL induced much stronger cytotoxicity and apoptosis to beta-cell lines CM and HP62 than did FasL, TNF-α, LTα1β2, LTα2β1, LIGHT, and IFN-γ. The cytotoxicity and apoptosis induced by TRAIL to beta-cell lines CM were inhibited competitively by soluble TRAIL receptors, R1, R2, R3 or R4. Treatment of these beta cells with antibodies against TRAIL receptors was able to block the cytotoxicity of TRAIL to these cells. Beta-cell antigen-specific CTL (CD4 + and CD8 + ) clones express TRAIL, suggesting that these cells are potential sources of TRAIL-inducing betacell destruction. Normal primary islet cells from most donors are resistant to the cytotoxicity mediated by TRAIL. However, treatment with an inhibitor of protein synthesis (cycloheximide) or with an enzyme (PI-PLC) that can remove TRAIL-R3 from the isletcell membrane was able to increase the susceptibility of TRAIL-resistant primary islet cells to the TRAIL death pathway. Conclusion/interpretation. The TRAIL death pathway is present and can function in human islet beta cells, but unidentified inhibitors of the TRAIL death pathway are present in normal islet cells. [Diabetologia (2002[Diabetologia ( ) 45:1678[Diabetologia ( -1688

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Tumor Necrosis Factor- -Activated Cell Death Pathways in NIT-1 Insulinoma Cells and Primary Pancreatic Cells

Cited by 57 publications

References 0 publications

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

TNFα and leptin inhibit basal and glucose-stimulated insulin secretion and gene transcription in the HIT-T15 pancreatic cells

TNF-Related Apoptosis-Inducing Ligand Death Pathway-Mediated Human Beta-Cell Destruction

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