A tripartite anoikis-like mechanism causes early isolated islet apoptosis

Thomas, F; Wu, Jiang; Contreras, Juan L.; Smyth, Cheryl A.; Bilbao, Guadalupe; He, Jin; Thomas, Judith M.

doi:10.1067/msy.2001.116413

Cited by 90 publications

(83 citation statements)

References 21 publications

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“…These facts increase the number of islet donors needed to treat a single diabetic transplant recipient. Loss of viability can also be attributed in part to detachment of the islets from the surrounding extracellular matrix that is essential for ␤-cell viability and function (13)(14)(15)(16)(17)(18). In addition, release of inflammatory cytokines such as IL-1␤ from the pancreatic tissue during the isolation procedure contributes to islet dysfunction and reduced mass.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to the adverse effects of IL-1␤, islets undergo enzymatic, osmotic, mechanical, and ischemic stresses during isolation, resulting in loss of viability, reduction of cell number, and initiation of apoptosis (10 -12). The loss of viability of isolated islets has been associated with detachment from the surrounding extracellular matrix, leading to activation of caspase-3 and NF-B (15)(16)(17)(18).…”

mentioning

confidence: 99%

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Protection of Islets by in SituPeptide-mediated Transduction of the IκB Kinase Inhibitor Nemo-binding Domain Peptide

Rehman¹,

Bertera²,

Bottino³

et al. 2003

Journal of Biological Chemistry

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We have previously demonstrated that adenoviral gene transfer of the NF-B inhibitor I B to human islets results in protection from interleukin (IL)-1␤-mediated dysfunction and apoptosis. Here we report that human and mouse islets can be efficiently transduced by a cationic peptide transduction domain (PTD-5) without impairment of islet function. PTD mediated delivery of a peptide inhibitor of the IL-1␤-induced I B kinase (IKK), derived from IKK␤ (NBD; Nemo-binding domain), and completely blocked the detrimental effects of IL-1␤ on islet function and NF-B activity, in a similar manner to Ad-I B. We also demonstrate that mouse islets can be transduced in situ by infusion of the transduction peptide through the bile duct prior to isolation, resulting in 40% peptide transduction of the ␤-cells. Delivery of the IKK inhibitor transduction fusion peptide (PTD-5-NBD) in situ to mouse islets resulted in improved islet function and viability after isolation. These results demonstrate the feasibility of using PTD-mediated delivery to transiently modify islets in situ to improve their viability and function during isolation, prior to transplantation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Protection of Islets by in SituPeptide-mediated Transduction of the IκB Kinase Inhibitor Nemo-binding Domain Peptide

Rehman¹,

Bertera²,

Bottino³

et al. 2003

Journal of Biological Chemistry

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“…However, the insulin independence rate after islet transplantation from one donor pancreas remains low. The low frequency of islet grafting is dependent on poor islet recovery from donors [4] and early islet loss during the first hours after grafting [5,6], termed primary graft nonfunction. Islet transplantation exposes cells to a variety of stressful stimuli, notably proinflammatory cytokines that encourage beta cell death and lead to early graft failure [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor

Noguchi

Nakai

Ueda³

et al. 2007

Diabetologia

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Aims/hypothesis Although application of the Edmonton protocol has markedly improved the outcome for pancreatic islet transplantation, the insulin independence rate after islet transplantation from one donor pancreas has remained low. During the isolation process and subsequent clinical transplantation, islets are subjected to severe adverse conditions that impair survival and ultimately contribute to graft failure. The aim of this study was to map the c-Jun NH 2 -terminal kinase (JNK) pathway that mediates islet loss during islet transplantation and to clarify whether intraportal injection with JNK inhibitor during islet transplantation can prevent islet graft loss. Methods We measured JNK activity in the liver, fat and muscle of diabetic mice and in the liver immediately after islet transplantation. We examined the effect of intraportal injection of JNK inhibitory peptide at islet transplantation. Results JNK activity became progressively higher at least until 24 h after transplantation. The cell-permeable peptide of JNK inhibitor was delivered not only in the liver but also in other insulin target organs, preventing JNK activation in the liver at least until 24 h after transplantation and reducing JNK activity in these insulin target organs. Moreover, the peptide inhibitor prevented islet graft loss immediately after transplantation and improved islet transplant outcome. Conclusions/interpretation These findings suggest that control of the JNK pathway is extremely important in islet transplantation and that intraportal injection of JNK inhibitor during islet transplantation (addition of JNK inhibitor to transplant media) could prevent the impairment of islet cells, leading to improved outcome for pancreatic islet transplantation.

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“…We used two T-cell clones, CD4 + THINSB1 and CD8 + THINSB2 for this study. These clones were derived from a new-onset Type I diabetic patient whose T cells responded well to beta-cell antigenic peptide INSB (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) [33,34,35]. Patient informed consent was obtained from the patient and patient's parents.…”

Section: Human Pancreatic Primary Islet Cells and Beta-cell Linesmentioning

confidence: 99%

“…The TRAIL pathway can induce apoptosis in a wide range of transformed tumor cells and virus-infected cells as well as normal human hepatocytes and brain cells [21,22]. A recent study showed that TRAIL pathway mediated early isolated normal islet apoptosis and inhibition of the TRAIL pathway might improve isolated islet survival and reduce functional islet mass loss [23]. However, little is known about the roles played by the TRAIL death pathway on beta-cell destruction in Type I diabetes.…”

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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A tripartite anoikis-like mechanism causes early isolated islet apoptosis

Cited by 90 publications

References 21 publications

Protection of Islets by in SituPeptide-mediated Transduction of the IκB Kinase Inhibitor Nemo-binding Domain Peptide

Protection of Islets by in SituPeptide-mediated Transduction of the IκB Kinase Inhibitor Nemo-binding Domain Peptide

Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor

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

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