c-Jun N-terminal kinase 1 is deleterious to the function and survival of murine pancreatic islets

J. L. Varona-Santos, A. Pileggi, Ruth Molano, N. Y. Sanabria, A. Ijaz, M. Atsushi, H. Ichii, Ricardo Pastori, Luca A Inverardi, Camillo Ricordi, Alessia Fornoni

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Aims/hypothesis: Inhibition of c-jun N-terminal kinase (JNK) favours pancreatic islet function and survival. Since two JNK isoforms are present in the pancreas (JNK1 and JNK2), we addressed their specific roles in experimental islet transplantation. Methods: C57BL/6J (wild-type [WT]), Jnk1 (also known as Mapk8)-/- and Jnk2 (also known as Mapk9)-/- mice were used as donor/recipients in a syngeneic islet transplantation model. Islet cell composition, function, viability, production of cytokines and of vascular endothelial growth factor (VEGF) were also studied in vitro. Results: Jnk1 -/- islets secreted more insulin in response to glucose and were more resistant to cytokine-induced cell death compared with WT and Jnk2 -/- islets (p<0.01). Cytokines reduced VEGF production in WT and Jnk2 -/- but not Jnk1 -/- islets; VEGF blockade restored Jnk1 -/- islet susceptibility to cytokine-induced cell death. Transplantation of Jnk1 -/- or WT islets into WT recipients made diabetic had similar outcomes. However, Jnk1 -/- recipients of WT islets had shorter time to diabetes reversal (17 vs 55 days in WT, p=0.033), while none of the Jnk2 -/- recipients had diabetes reversal (0% vs 71% in WT, p=0.0003). Co-culture of WT islets with macrophages from each strain revealed a discordant cytokine production. Conclusions/interpretation: We have shown a deleterious effect of JNK2 deficiency on islet graft outcome, most likely related to JNK1 activation, suggesting that specific JNK1 blockade may be superior to general JNK inhibition, particularly when administered to transplant recipients.

Original languageEnglish
Pages (from-to)2271-2280
Number of pages10
JournalDiabetologia
Volume51
Issue number12
DOIs
StatePublished - Dec 1 2008

Fingerprint

Mitogen-Activated Protein Kinase 8
Islets of Langerhans
Cytokines
Vascular Endothelial Growth Factor A
Islets of Langerhans Transplantation
Cell Death
Phosphotransferases
Isogeneic Transplantation
JNK Mitogen-Activated Protein Kinases
Coculture Techniques
Pancreas
Protein Isoforms
Transplantation
Macrophages
Tissue Donors
Insulin
Transplants
Glucose

Keywords

  • Cytokines
  • Gene knockout
  • Inflammation
  • Insulin secretion
  • Islet function
  • Islet transplantation
  • JNK
  • MAPK

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Varona-Santos, J. L., Pileggi, A., Molano, R., Sanabria, N. Y., Ijaz, A., Atsushi, M., ... Fornoni, A. (2008). c-Jun N-terminal kinase 1 is deleterious to the function and survival of murine pancreatic islets. Diabetologia, 51(12), 2271-2280. https://doi.org/10.1007/s00125-008-1169-7

c-Jun N-terminal kinase 1 is deleterious to the function and survival of murine pancreatic islets. / Varona-Santos, J. L.; Pileggi, A.; Molano, Ruth; Sanabria, N. Y.; Ijaz, A.; Atsushi, M.; Ichii, H.; Pastori, Ricardo; Inverardi, Luca A; Ricordi, Camillo; Fornoni, Alessia.

In: Diabetologia, Vol. 51, No. 12, 01.12.2008, p. 2271-2280.

Research output: Contribution to journalArticle

Varona-Santos, JL, Pileggi, A, Molano, R, Sanabria, NY, Ijaz, A, Atsushi, M, Ichii, H, Pastori, R, Inverardi, LA, Ricordi, C & Fornoni, A 2008, 'c-Jun N-terminal kinase 1 is deleterious to the function and survival of murine pancreatic islets', Diabetologia, vol. 51, no. 12, pp. 2271-2280. https://doi.org/10.1007/s00125-008-1169-7
Varona-Santos JL, Pileggi A, Molano R, Sanabria NY, Ijaz A, Atsushi M et al. c-Jun N-terminal kinase 1 is deleterious to the function and survival of murine pancreatic islets. Diabetologia. 2008 Dec 1;51(12):2271-2280. https://doi.org/10.1007/s00125-008-1169-7
Varona-Santos, J. L. ; Pileggi, A. ; Molano, Ruth ; Sanabria, N. Y. ; Ijaz, A. ; Atsushi, M. ; Ichii, H. ; Pastori, Ricardo ; Inverardi, Luca A ; Ricordi, Camillo ; Fornoni, Alessia. / c-Jun N-terminal kinase 1 is deleterious to the function and survival of murine pancreatic islets. In: Diabetologia. 2008 ; Vol. 51, No. 12. pp. 2271-2280.
@article{38d96ceb3e60492d82e6e705f46573b5,
title = "c-Jun N-terminal kinase 1 is deleterious to the function and survival of murine pancreatic islets",
abstract = "Aims/hypothesis: Inhibition of c-jun N-terminal kinase (JNK) favours pancreatic islet function and survival. Since two JNK isoforms are present in the pancreas (JNK1 and JNK2), we addressed their specific roles in experimental islet transplantation. Methods: C57BL/6J (wild-type [WT]), Jnk1 (also known as Mapk8)-/- and Jnk2 (also known as Mapk9)-/- mice were used as donor/recipients in a syngeneic islet transplantation model. Islet cell composition, function, viability, production of cytokines and of vascular endothelial growth factor (VEGF) were also studied in vitro. Results: Jnk1 -/- islets secreted more insulin in response to glucose and were more resistant to cytokine-induced cell death compared with WT and Jnk2 -/- islets (p<0.01). Cytokines reduced VEGF production in WT and Jnk2 -/- but not Jnk1 -/- islets; VEGF blockade restored Jnk1 -/- islet susceptibility to cytokine-induced cell death. Transplantation of Jnk1 -/- or WT islets into WT recipients made diabetic had similar outcomes. However, Jnk1 -/- recipients of WT islets had shorter time to diabetes reversal (17 vs 55 days in WT, p=0.033), while none of the Jnk2 -/- recipients had diabetes reversal (0{\%} vs 71{\%} in WT, p=0.0003). Co-culture of WT islets with macrophages from each strain revealed a discordant cytokine production. Conclusions/interpretation: We have shown a deleterious effect of JNK2 deficiency on islet graft outcome, most likely related to JNK1 activation, suggesting that specific JNK1 blockade may be superior to general JNK inhibition, particularly when administered to transplant recipients.",
keywords = "Cytokines, Gene knockout, Inflammation, Insulin secretion, Islet function, Islet transplantation, JNK, MAPK",
author = "Varona-Santos, {J. L.} and A. Pileggi and Ruth Molano and Sanabria, {N. Y.} and A. Ijaz and M. Atsushi and H. Ichii and Ricardo Pastori and Inverardi, {Luca A} and Camillo Ricordi and Alessia Fornoni",
year = "2008",
month = "12",
day = "1",
doi = "10.1007/s00125-008-1169-7",
language = "English",
volume = "51",
pages = "2271--2280",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer Verlag",
number = "12",

}

TY - JOUR

T1 - c-Jun N-terminal kinase 1 is deleterious to the function and survival of murine pancreatic islets

AU - Varona-Santos, J. L.

AU - Pileggi, A.

AU - Molano, Ruth

AU - Sanabria, N. Y.

AU - Ijaz, A.

AU - Atsushi, M.

AU - Ichii, H.

AU - Pastori, Ricardo

AU - Inverardi, Luca A

AU - Ricordi, Camillo

AU - Fornoni, Alessia

PY - 2008/12/1

Y1 - 2008/12/1

N2 - Aims/hypothesis: Inhibition of c-jun N-terminal kinase (JNK) favours pancreatic islet function and survival. Since two JNK isoforms are present in the pancreas (JNK1 and JNK2), we addressed their specific roles in experimental islet transplantation. Methods: C57BL/6J (wild-type [WT]), Jnk1 (also known as Mapk8)-/- and Jnk2 (also known as Mapk9)-/- mice were used as donor/recipients in a syngeneic islet transplantation model. Islet cell composition, function, viability, production of cytokines and of vascular endothelial growth factor (VEGF) were also studied in vitro. Results: Jnk1 -/- islets secreted more insulin in response to glucose and were more resistant to cytokine-induced cell death compared with WT and Jnk2 -/- islets (p<0.01). Cytokines reduced VEGF production in WT and Jnk2 -/- but not Jnk1 -/- islets; VEGF blockade restored Jnk1 -/- islet susceptibility to cytokine-induced cell death. Transplantation of Jnk1 -/- or WT islets into WT recipients made diabetic had similar outcomes. However, Jnk1 -/- recipients of WT islets had shorter time to diabetes reversal (17 vs 55 days in WT, p=0.033), while none of the Jnk2 -/- recipients had diabetes reversal (0% vs 71% in WT, p=0.0003). Co-culture of WT islets with macrophages from each strain revealed a discordant cytokine production. Conclusions/interpretation: We have shown a deleterious effect of JNK2 deficiency on islet graft outcome, most likely related to JNK1 activation, suggesting that specific JNK1 blockade may be superior to general JNK inhibition, particularly when administered to transplant recipients.

AB - Aims/hypothesis: Inhibition of c-jun N-terminal kinase (JNK) favours pancreatic islet function and survival. Since two JNK isoforms are present in the pancreas (JNK1 and JNK2), we addressed their specific roles in experimental islet transplantation. Methods: C57BL/6J (wild-type [WT]), Jnk1 (also known as Mapk8)-/- and Jnk2 (also known as Mapk9)-/- mice were used as donor/recipients in a syngeneic islet transplantation model. Islet cell composition, function, viability, production of cytokines and of vascular endothelial growth factor (VEGF) were also studied in vitro. Results: Jnk1 -/- islets secreted more insulin in response to glucose and were more resistant to cytokine-induced cell death compared with WT and Jnk2 -/- islets (p<0.01). Cytokines reduced VEGF production in WT and Jnk2 -/- but not Jnk1 -/- islets; VEGF blockade restored Jnk1 -/- islet susceptibility to cytokine-induced cell death. Transplantation of Jnk1 -/- or WT islets into WT recipients made diabetic had similar outcomes. However, Jnk1 -/- recipients of WT islets had shorter time to diabetes reversal (17 vs 55 days in WT, p=0.033), while none of the Jnk2 -/- recipients had diabetes reversal (0% vs 71% in WT, p=0.0003). Co-culture of WT islets with macrophages from each strain revealed a discordant cytokine production. Conclusions/interpretation: We have shown a deleterious effect of JNK2 deficiency on islet graft outcome, most likely related to JNK1 activation, suggesting that specific JNK1 blockade may be superior to general JNK inhibition, particularly when administered to transplant recipients.

KW - Cytokines

KW - Gene knockout

KW - Inflammation

KW - Insulin secretion

KW - Islet function

KW - Islet transplantation

KW - JNK

KW - MAPK

UR - http://www.scopus.com/inward/record.url?scp=55649092238&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=55649092238&partnerID=8YFLogxK

U2 - 10.1007/s00125-008-1169-7

DO - 10.1007/s00125-008-1169-7

M3 - Article

C2 - 18853132

AN - SCOPUS:55649092238

VL - 51

SP - 2271

EP - 2280

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 12

ER -