TY - JOUR
T1 - Intracellular stress signaling pathways activated during human islet preparation and following acute cytokine exposure
AU - Abdelli, Saida
AU - Ansite, Jeff
AU - Roduit, Raphael
AU - Borsello, Tiziana
AU - Matsumoto, Ippei
AU - Sawada, Toshiya
AU - Allaman-Pillet, Nathalie
AU - Henry, Hugues
AU - Beckmann, Jacques S.
AU - Hering, Bernhard J.
AU - Bonny, Christophe
PY - 2004/11
Y1 - 2004/11
N2 - 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 NH2-terminal kinase (JNK)/p38 - c-fos| and the |nuclear factor-κB (NF-κB) → iNOS| module. Cytokines activate the |NF-κB → 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.
AB - 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 NH2-terminal kinase (JNK)/p38 - c-fos| and the |nuclear factor-κB (NF-κB) → iNOS| module. Cytokines activate the |NF-κB → 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.
UR - http://www.scopus.com/inward/record.url?scp=7044249537&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=7044249537&partnerID=8YFLogxK
U2 - 10.2337/diabetes.53.11.2815
DO - 10.2337/diabetes.53.11.2815
M3 - Article
C2 - 15504961
AN - SCOPUS:7044249537
VL - 53
SP - 2815
EP - 2823
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 11
ER -