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Diabetologia
Published in: Diabetologia 3/2007

01-03-2007 | Article

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

Authors: H. Noguchi, Y. Nakai, M. Ueda, Y. Masui, S. Futaki, N. Kobayashi, S. Hayashi, S. Matsumoto

Published in: Diabetologia | Issue 3/2007

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Abstract

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 NH2-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.
Literature
1.
Shapiro AM, Lakey JR, Ryan EA et al (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230–238PubMedCrossRef
2.
Matsumoto S, Okitsu T, Iwanaga Y et al (2005) Insulin independence after living-donor distal pancreatectomy and islet allotransplantation. Lancet 365:1642–1644PubMedCrossRef
3.
Noguchi H, Iwanaga Y, Okitsu T et al (2006) Evaluation of islet transplantation from non-heart beating donors. Am J Transplant 6:2476–2482PubMedCrossRef
4.
Paraskevas S, Maysinger D, Wang R, Duguid TP, Rosenberg L (2000) Cell loss in isolated human islets occurs by apoptosis. Pancreas 20:270–276PubMedCrossRef
5.
Thomas F, Wu J, Contreras JL et al (2001) A tripartite anoikis-like mechanism causes early isolated islet apoptosis. Surgery 130:333–338PubMedCrossRef
6.
Davalli AM, Scaglia L, Zangen DH, Hollister J, Bonner-Weir S, Weir GC (1996) Vulnerability of islets in the immediate posttransplantation period. Dynamic changes in structure and function. Diabetes 45:1161–1167PubMed
7.
Rabinovitch A, Sorensen O, Suarez-Pinzon WL, Power RF, Rajotte RV, Bleackley RC (1994) Analysis of cytokine mRNA expression in syngeneic islet grafts of NOD mice: interleukin 2 and interferon gamma mRNA expression correlate with graft rejection and interleukin 10 with graft survival. Diabetologia 37:833–837PubMed
8.
Faust A, Rothe H, Schade U, Lampeter E, Kolb H (1996) Primary nonfunction of islet grafts in autoimmune diabetic nonobese diabetic mice is prevented by treatment with interleukin-4 and interleukin-10. Transplantation 62:648–652PubMedCrossRef
9.
Dobson T, Fraga D, Saba C, Bryer-Ash M, Gaber AO, Gerling IC (2000) Human pancreatic islets transfected to produce an inhibitor of TNF are protected against destruction by human leukocytes. Cell Transplant 9:857–865PubMed
10.
Thomas D, Yang H, Boffa DJ et al (2002) Proapoptotic Bax is hyperexpressed in isolated human islets compared with antiapoptotic Bcl-2. Transplantation 74:1489–1496PubMedCrossRef
11.
Rehman KK, Bertera S, Bottino R et al (2003) Protection of islets by in situ peptide-mediated transduction of the Ikappa B kinase inhibitor Nemo-binding domain peptide. J Biol Chem 278:9862–9868PubMedCrossRef
12.
Abdelli S, Ansite J, Roduit R et al (2004) Intracellular stress signaling pathways activated during human islet preparation and following acute cytokine exposure. Diabetes 53:2815–2823PubMed
13.
Bennet W, Sundberg B, Groth CG et al (1999) Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes 48:1907–1914PubMed
14.
Badet L, Titus T, Metzen E et al (2002) The interaction between primate blood and mouse islets induces accelerated clotting with islet destruction. Xenotransplantation 9:91–96PubMedCrossRef
15.
Moberg L, Johansson H, Lukinius A et al (2002) Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet 360:2039–2045PubMedCrossRef
16.
Bottino R, Fernandez LA, Ricordi C et al (1998) Transplantation of allogeneic islets of Langerhans in the rat liver: effects of macrophage depletion on graft survival and microenvironment activation. Diabetes 47:316–323PubMed
17.
Fontaine MJ, Blanchard J, Rastellini C, Lazda V, Herold KC, Pollak R (2002) Pancreatic islets activate portal vein endothelial cells in vitro. Ann Clin Lab Sci 32:352–361PubMed
18.
Arita S, Une S, Ohtsuka S et al (1998) Prevention of primary islet isograft nonfunction in mice with pravastatin. Transplantation 65:1429–1433PubMedCrossRef
19.
Kaufman DB, Gores PF, Field MJ et al (1994) Effect of 15-deoxyspergualin on immediate function and long-term survival of transplanted islets in murine recipients of a marginal islet mass. Diabetes 43:778–783PubMed
20.
Xenos ES, Stevens RB, Sutherland DE et al (1994) The role of nitric oxide in IL-1 beta-mediated dysfunction of rodent islets of Langerhans: implications for the function of intrahepatic islet grafts. Transplantation 57:1208–1212PubMedCrossRef
21.
Boulton TG, Nye SH, Robbins DJ et al (1991) ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65:663–675PubMedCrossRef
22.
Keesler GA, Bray J, Hunt J et al (1998) Purification and activation of recombinant p38 isoforms alpha, beta, gamma, and delta. Protein Expr Purif 14:221–228PubMedCrossRef
23.
Davis RJ (1999) Signal transduction by the c-Jun N-terminal kinase. Biochem Soc Symp 64:1–12PubMed
24.
Ammendrup A, Maillard A, Nielsen K et al (2000) The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic β-cells. Diabetes 49:1468–1476PubMed
25.
Negri S, Oberson A, Steinmann M et al (2000) cDNA cloning and mapping of a novel islet-brain/JNK interacting protein. Genomics 64:324–330PubMedCrossRef
26.
Hirosumi J, Tuncman G, Chang L et al (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336PubMedCrossRef
27.
Aguirre V, Uchida T, Yenush L, Davis R, White MF (2000) The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J Biol Chem 275:9047–9054PubMedCrossRef
28.
Manning AM, Davis R (2003) Targeting JNK for therapeutic benefit: from junk to gold? Nature Rev Drug Discov 2:554–565CrossRef
29.
Kaneto H, Xu G, Fujii N, Kim S, Bonner-Weir S, Weir GC (2002) Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J Biol Chem 277:30010–30018PubMedCrossRef
30.
Kawamori D, Kajimoto Y, Kaneto H et al (2003) Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun NH(2)-terminal kinase. Diabetes 52:2896–2904PubMed
31.
Noguchi H, Nakai Y, Matsumoto S et al (2005) Cell permeable peptide of JNK inhibitor prevents islet apoptosis immediately after isolation and improves islet graft function. Am J Transplant 5:1848–1855PubMedCrossRef
32.
Noguchi H, Kobayashi N, Westerman KA et al (2002) Controlled expansion of human endothelial cell populations by Cre-loxP-based reversible immortalization. Hum Gene Ther 13:321–334PubMedCrossRef
33.
Noguchi H, Matsushita M, Okitsu T et al (2004) A new cell-permeable peptide allows successful allogeneic islet transplantation in mice. Nat Med 10:305–309PubMedCrossRef
34.
Corbett JA, Wang JL, Sweetland MA, Lancaster JR Jr, McDaniel ML (1992) Interleukin 1 beta induces the formation of nitric oxide by beta-cells purified from rodent islets of Langerhans. Evidence for the beta-cell as a source and site of action of nitric oxide. J Clin Invest 90:2384–2391PubMedCrossRef
35.
Kaneto H, Fujii J, Seo HG et al (1995) Apoptotic cell death triggered by nitric oxide in pancreatic beta-cells. Diabetes 44:733–738PubMed
36.
Bonny C, Oberson A, Steinmann M, Schorderet DF, Nicod P, Waeber G (2000) IB1 reduces cytokine-induced apoptosis of insulin-secreting cells. J Biol Chem 275:16466–16472PubMedCrossRef
37.
Kaneto H, Nakatani Y, Miyatsuka T et al (2004) Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide. Nat Med 10:1128–1132PubMedCrossRef
38.
Noguchi H, Bonner-Weir S, Wei FY, Matsushita M, Matsumoto S (2005) BETA2/NeuroD protein can be transduced into cells due to an arginine- and lysine-rich sequence. Diabetes 54:2859–2866PubMed
39.
Noguchi, H, Kaneto H, Weir GC, Bonner-Weir S (2003) PDX-1 protein containing its own antennapedia-like protein transduction domain can transduce pancreatic duct and islet cells. Diabetes 52:1732–1737PubMed
40.
Noguchi H, Matsumoto S, Okitsu T et al (2005) PDX-1 protein is internalized by lipid raft-dependent macropinocytosis. Cell Transplant 14:637–645PubMed
41.
Elliott G, O’Hare P (1997) Intercellular trafficking and protein delivery by a herpesvirus structural protein. Cell 88:223–233PubMedCrossRef
42.
Bonny C, Oberson A, Negri S, Sauser C, Schorderet DF (2001) Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death. Diabetes 50:77–82PubMed
43.
Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF (1999) In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285:1569–1572PubMedCrossRef
44.
Embury J, Klein D, Pileggi A et al (2001) Proteins linked to a protein transduction domain efficiently transduce pancreatic islets. Diabetes 50:1706–1713PubMed
45.
Ribeiro MM, Klein D, Pileggi A et al (2003) Heme oxygenase-1 fused to a TAT peptide transduces and protects pancreatic beta-cells. Biochem Biophys Res Commun 305:876–881PubMedCrossRef
46.
Klein D, Ribeiro MM, Mendoza V et al (2004) Delivery of Bcl-XL or its BH4 domain by protein transduction inhibits apoptosis in human islets. Biochem Biophys Res Commun 323:473–478PubMedCrossRef
47.
Futaki S, Suzuki T, Ohashi W et al (2001) Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J Biol Chem 276:5836–5840PubMedCrossRef
Metadata
Title
Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor
Authors
H. Noguchi
Y. Nakai
M. Ueda
Y. Masui
S. Futaki
N. Kobayashi
S. Hayashi
S. Matsumoto
Publication date
01-03-2007
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 3/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-006-0563-2

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