nach oben

Diabetologia

Erschienen in:

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

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

Erschienen in: Diabetologia | Ausgabe 3/2007

Einloggen, um Zugang zu erhalten

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.

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

Matsumoto S, Okitsu T, Iwanaga Y et al (2005) Insulin independence after living-donor distal pancreatectomy and islet allotransplantation. Lancet 365:1642–1644PubMedCrossRef

Noguchi H, Iwanaga Y, Okitsu T et al (2006) Evaluation of islet transplantation from non-heart beating donors. Am J Transplant 6:2476–2482PubMedCrossRef

Paraskevas S, Maysinger D, Wang R, Duguid TP, Rosenberg L (2000) Cell loss in isolated human islets occurs by apoptosis. Pancreas 20:270–276PubMedCrossRef

Thomas F, Wu J, Contreras JL et al (2001) A tripartite anoikis-like mechanism causes early isolated islet apoptosis. Surgery 130:333–338PubMedCrossRef

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

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

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

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

Titel: Activation of c-Jun NH2-terminal kinase (JNK) pathway during islet transplantation and prevention of islet graft loss by intraportal injection of JNK inhibitor
verfasst von: H. Noguchi
Y. Nakai
M. Ueda
Y. Masui
S. Futaki
N. Kobayashi
S. Hayashi
S. Matsumoto
Publikationsdatum: 01.03.2007
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 3/2007
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0563-2

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

25.04.2024 Allergien und Intoleranzreaktionen Nachrichten

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2007

Regulation of pancreatic endocrine cell differentiation by sulphated proteoglycans

Soluble thrombomodulin as a predictor of type 2 diabetes: results from the MONICA/KORA Augsburg case–cohort study, 1984–1998

A. Veves, J.M. Giurini, F.W. LoGerfo (eds) The diabetic foot (second edn). Humana Press, Totowa, New Jersey, 2006

Studies of the associations between functional β2-adrenergic receptor variants and obesity, hypertension and type 2 diabetes in 7,808 white subjects

Pre-eclampsia and the later development of type 2 diabetes in mothers and their children: an intergenerational study from the Walker cohort