Pancreatic islet transplantation may successfully restore normoglycemia in type 1 diabetic patients. However, successful grafting requires transplantation of a sufficient number of islets, usually requiring two or more donors. During the isolation process and following clinical transplantation, islets are subjected to severe adverse conditions that impair survival and ultimately contribute to graft failure. Here, we have mapped the major intracellular stress-signaling pathways that may mediate human islet loss during isolation and following cytokine attack. We found that the isolation procedure potently recruits two pathways consisting of |mitogen-activated protein kinase kinase (MKK)7 --> Jun NH(2)-terminal kinase (JNK)/p38 --> c-fos| and the |nuclear factor-kappaB (NF-kappaB) --> iNOS| module. Cytokines activate the |NF-kappaB --> iNOS| and |MKK4/MKK3/6 --> JNK/p38| pathways without recruitment of c-fos. Culturing the islets for 48 h after isolation allows for the activated pathways to return to background levels, with expression of MKK7 becoming undetectable. These data indicate that isolation and cytokines recruit different death pathways. Therefore, strategies might be rationally developed to avoid possible synergistic activation of these pathways in mediating islet loss during isolation and following grafting.

Intracellular stress signaling pathways activated during human islet preparation and following acute cytokine exposure / S. Abdelli, J. Ansite, R. Roduit, T. Borsello, I. Matsumoto, T. Sawada, N. Allaman Pillet, H. Henry, J.S. Beckmann, B.J. Hering, C. Bonny. - In: DIABETES. - ISSN 0012-1797. - 53:11(2004 Nov), pp. 2815-2823. [10.2337/diabetes.53.11.2815]

Intracellular stress signaling pathways activated during human islet preparation and following acute cytokine exposure

T. Borsello;
2004

Abstract

Pancreatic islet transplantation may successfully restore normoglycemia in type 1 diabetic patients. However, successful grafting requires transplantation of a sufficient number of islets, usually requiring two or more donors. During the isolation process and following clinical transplantation, islets are subjected to severe adverse conditions that impair survival and ultimately contribute to graft failure. Here, we have mapped the major intracellular stress-signaling pathways that may mediate human islet loss during isolation and following cytokine attack. We found that the isolation procedure potently recruits two pathways consisting of |mitogen-activated protein kinase kinase (MKK)7 --> Jun NH(2)-terminal kinase (JNK)/p38 --> c-fos| and the |nuclear factor-kappaB (NF-kappaB) --> iNOS| module. Cytokines activate the |NF-kappaB --> iNOS| and |MKK4/MKK3/6 --> JNK/p38| pathways without recruitment of c-fos. Culturing the islets for 48 h after isolation allows for the activated pathways to return to background levels, with expression of MKK7 becoming undetectable. These data indicate that isolation and cytokines recruit different death pathways. Therefore, strategies might be rationally developed to avoid possible synergistic activation of these pathways in mediating islet loss during isolation and following grafting.
nitric-oxide synthase; I-kappa-B; human pancreatic-islets; cold-storage method; protein-kinase; cell-death; beta-cells; transcription factor; transduction pathway; primary nonfunction
Settore BIO/14 - Farmacologia
Settore BIO/16 - Anatomia Umana
nov-2004
Article (author)
File in questo prodotto:
File Dimensione Formato  
Diabetes-2004-Abdelli-2815-23.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 469.85 kB
Formato Adobe PDF
469.85 kB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/347904
Citazioni
  • ???jsp.display-item.citation.pmc??? 58
  • Scopus 151
  • ???jsp.display-item.citation.isi??? 146
social impact