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

被引：21

作者：

Varona-Santos, J. L. ^{[1
]}

Pileggi, A. ^{[1
,2
]}

Molano, R. D. ^{[1
]}

Sanabria, N. Y. ^{[1
]}

Ijaz, A. ^{[1
,3
]}

Atsushi, M. ^{[1
]}

Ichii, H. ^{[1
,2
,4
]}

Pastori, R. L. ^{[1
]}

Inverardi, L. ^{[1
]}

Ricordi, C. ^{[1
,2
]}

Fornoni, A. ^{[1
,3
]}

机构：

[1] Univ Miami, Diabet Res Inst, Miller Sch Med, Miami, FL 33136 USA

[2] Univ Miami, DeWitt Daughtry Dept Surg, Miller Sch Med, Miami, FL 33136 USA

[3] Univ Miami, Div Nephrol & Hypertens, Miller Sch Med, Miami, FL 33136 USA

[4] Univ Miami, Jackson Mem Hosp, Miller Sch Med, Miami, FL 33136 USA

来源：

DIABETOLOGIA | 2008年 / 51卷 / 12期

关键词：

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

D O I：

10.1007/s00125-008-1169-7

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. 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. 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. 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.

引用

页码：2271 / 2280

页数：10

共 38 条

[1] The c-Jun N-terminal kinase JNK participates in cytokineand isolation stress-induced rat pancreatic islet apoptosis [J].

Abdelli, S. ;

Abderrahmani, A. ;

Hering, B. J. ;

Beckmann, J. S. ;

Bonny, C. .

DIABETOLOGIA, 2007, 50 (08) :1660-1669

[2] Intracellular stress signaling pathways activated during human islet preparation and following acute cytokine exposure [J].

Abdelli, S ;

Ansite, J ;

Roduit, R ;

Borsello, T ;

Matsumoto, I ;

Sawada, T ;

Allaman-Pillet, N ;

Henry, H ;

Beckmann, JS ;

Hering, BJ ;

Bonny, C .

DIABETES, 2004, 53 (11) :2815-2823

[3] Cross-talk between phosphatidylinositol 3-kinase/AKT and c-Jun NH2-terminal kinase mediates survival of isolated human islets [J].

Aikin, R ;

Maysinger, D ;

Rosenberg, L .

ENDOCRINOLOGY, 2004, 145 (10) :4522-4531

[4] The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic β-cells [J].

Ammendrup, A ;

Maillard, A ;

Nielsen, K ;

Andersen, NA ;

Serup, P ;

Madsen, OD ;

Mandrup-Poulsen, T ;

Bonny, C .

DIABETES, 2000, 49 (09) :1468-1476

[5] Would blockage of cytokines improve the outcome of pancreatic islet transplantation? [J].

Amoli, MM ;

Larijani, B .

MEDICAL HYPOTHESES, 2006, 66 (04) :816-819

[6] Tumor necrosis factor-α-induced reactive oxygen species formation is mediated by JNK1-dependent ferritin degradation and elevation of labile iron pool [J].

Antosiewicz, Jedrzej ;

Ziolkowski, Wieslaw ;

Kaczor, Jan Jacek ;

Herman-Antosiewicz, Anna .

FREE RADICAL BIOLOGY AND MEDICINE, 2007, 43 (02) :265-270

[7] CYTOTOXICITY OF HUMAN PI-7 INTERLEUKIN-1 FOR PANCREATIC-ISLETS OF LANGERHANS [J].

BENDTZEN, K ;

MANDRUPPOULSEN, T ;

NERUP, J ;

NIELSEN, JH ;

DINARELLO, CA ;

SVENSON, M .

SCIENCE, 1986, 232 (4757) :1545-1547

[8] Inhibitors of c-Jun N-terminal kinases-JuNK no more? [J].

Bogoyevitch, Marie A. ;

Arthur, Peter G. .

BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 2008, 1784 (01) :76-93

[9] The isoform-specific functions of the c-Jun N-terminal kinases (JNKs): differences revealed by gene targeting [J].

Bogoyevitch, Marie A. .

BIOESSAYS, 2006, 28 (09) :923-934

[10] Cell-permeable peptide inhibitors of JNK novel blockers of β-cell death [J].

Bonny, C ;

Oberson, A ;

Negri, S ;

Sauser, C ;

Schorderet, DF .

DIABETES, 2001, 50 (01) :77-82

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