Discrete and Complementary Mechanisms of Protection of β-Cells Against Cytokine-Induced and Oxidative Damage Achieved by bcl-2 Overexpression and a Cytokine Selection Strategy

Tran, Veronique V.; Chen, Guoxun; Newgard, Christopher B.; Hohmeier, Hans E.

doi:10.2337/diabetes.52.6.1423

Cited by 48 publications

(41 citation statements)

References 57 publications

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“…We found that bcl-2-overexpressing cells were highly resistant to the cytotoxic effects of ROS and RNS, but only modestly protected against high concentrations of IL-1b þ IFN-g, while the converse is true of INS-1-derived cell lines subjected to the cytokine selection procedure. 31 We also found that the combination of bcl-2 expression and cytokine selection confers a broader spectrum of resistance than either procedure alone, such that the resultant cells are highly resistant to incubation with high doses of cytokines or ROS/RNS. INS-1-derived cells with combined bcl-2 expression and cytokine selection were also more resistant to damage induced by co-culture with mitogen-activated PBMC.…”

Section: Development Of Methods For Protecting Insulinoma Cell Lines mentioning

confidence: 85%

“…[32][33][34][35] Consistent with this model, we observed lower levels of Ik-Ba in our bcl-2-overexpressing, selected cell lines than in cells lacking bcl-2 expression and subjected to the selection procedure. 31 We suggest that chronic activation of NF-kB may lead to increased expression of genes with cytoprotective function such as Hsp27, Hsp70, and MnSOD. 36 Further studies will be required to fully develop these ideas.…”

Section: Development Of Methods For Protecting Insulinoma Cell Lines mentioning

confidence: 99%

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Inflammatory mechanisms in diabetes: lessons from the β-cell

et al. 2003

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Inflammation plays an important role in the destruction of pancreatic islet b-cells that leads to type I diabetes. This involves infiltration of T-cells and macrophages into the islets and local production of inflammatory cytokines such as interleukin (IL)-1b, tumor necrosis factor (TNF)-a, and interferon (IFN)-g. Our laboratory has developed several strategies for protecting b-cells against oxidative stress and cytokine-induced cytotoxicity. These include a cytokine selection strategy that results in cell lines that are resistant to the combined effects of IL-1b þ IFN-g. More recently, we have combined the cytokine selection procedure with overexpression of the antiapoptotic gene bcl-2, resulting in cell lines with greater resistance to oxidative stress and cytokine-induced damage than achieved with either procedure alone. This article summarizes this work and the remarkably divergent mechanisms by which protection is achieved in the different model systems. We also discuss the potential relevance of insights gained from these approaches for enhancing islet cell survival and function in both major forms of diabetes.

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Section: Development Of Methods For Protecting Insulinoma Cell Lines mentioning

confidence: 85%

Section: Development Of Methods For Protecting Insulinoma Cell Lines mentioning

confidence: 99%

Inflammatory mechanisms in diabetes: lessons from the β-cell

et al. 2003

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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: 98%

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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“…We have previously described cytokine-resistant INS-1-derived ␤-cell lines, developed via a selection strategy involving long-term culture in increasing doses of IL-1␤ plus ␥-IFN (16,22). We compared the effects of cytokines with those of camptothecin and etoposide, topoisomerase I and II inhibitors and known inducers of apoptosis (21,23), in a cell line selected for cytokine resistance (line 833/15) versus a cell line that did not undergo selection (line 832/13).…”

Section: Resultsmentioning

confidence: 99%

“…Stable overexpression of bcl-2 in rodent ␤-cell lines (22) and virally mediated overexpression of bcl-2 in human pancreatic islets (53) appear to confer protection against basal levels of apoptosis (i.e., normal cell turnover) and apoptosis induced by other mechanisms. However, stable overexpression of bcl-2 provides significant protection against cell death induced by reactive oxygen species but minimal protection against cytokine damage (22). Moreover, bcl-2 expression is not effective in protection of islets when transplanted into rodent models of autoimmune diabetes (54), suggesting that other, nonapoptotic mechanisms of cell damage play an important role.…”

Section: Discussionmentioning

confidence: 99%

Pro- and Antiapoptotic Proteins Regulate Apoptosis but Do Not Protect Against Cytokine-Mediated Cytotoxicity in Rat Islets and β-Cell Lines

Collier

Fueger²,

Hohmeier³

et al. 2006

Diabetes

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Type 1 diabetes results from islet ␤-cell death and dysfunction induced by an autoimmune mechanism. Proinflammatory cytokines such as interleukin-1␤ and ␥-interferon are mediators of this ␤-cell cytotoxicity, but the mechanism by which damage occurs is not well understood. In the current study, we present multiple lines of evidence supporting the conclusion that cytokine-induced killing of rat ␤-cells occurs predominantly by a nonapoptotic mechanism, including the following: 1) A rat ␤-cell line selected for resistance to cytokine-induced cytotoxicity (833/15) is equally sensitive to killing by the apoptosis-inducing agents camptothecin and etoposide as a cytokine-sensitive cell line (832/ 13). 2) Overexpression of a constitutively active form of the antiapoptotic protein kinase Akt1 in 832/13 cells provides significant protection against cell killing induced by camptothecin and etoposide but no protection against cytokine-mediated damage. 3) Small interfering RNA-mediated suppression of the proapoptotic protein Bax enhances viability of 832/13 cells upon exposure to the known apoptosis-inducing drugs but not the inflammatory cytokines. 4) Exposure of primary rat islets or 832/13 cells to the inflammatory cytokines causes cell death as evidenced by the release of adenylate kinase activity into the cell medium, with no attendant increase in caspase 3 activation or annexin V staining. In contrast, camptothecin-and etoposide-induced killing is associated with robust increases in caspase 3 activation and annexin V staining. 5) Camptothecin increases cellular ATP levels, whereas inflammatory cytokines lower ATP levels in both ␤-cell lines and primary islets. We conclude that proinflammatory cytokines cause ␤-cell cytotoxicity primarily through a nonapoptotic mechanism linked to a decline in ATP levels.

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Discrete and Complementary Mechanisms of Protection of β-Cells Against Cytokine-Induced and Oxidative Damage Achieved by bcl-2 Overexpression and a Cytokine Selection Strategy

Cited by 48 publications

References 57 publications

Inflammatory mechanisms in diabetes: lessons from the β-cell

Inflammatory mechanisms in diabetes: lessons from the β-cell

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

Pro- and Antiapoptotic Proteins Regulate Apoptosis but Do Not Protect Against Cytokine-Mediated Cytotoxicity in Rat Islets and β-Cell Lines

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