Related Experiment Video
Updated: Jun 29, 2026
Methods to Assess Beta Cell Death Mediated by Cytotoxic T Lymphocytes
Published on: June 16, 2011
c-Jun N-terminal kinase 1 is deleterious to the function and survival of murine pancreatic islets
J L Varona-Santos1, A Pileggi, R D Molano
1Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, FL 33136, USA.
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.
Insights
JNK2 deficiency impairs islet transplantation outcomes, while JNK1 deficiency improves islet function and survival. Targeting JNK1 specifically may enhance islet transplant success in recipients.
Area of Science:
- Immunology
- Endocrinology
- Molecular Biology
Background:
- c-jun N-terminal kinase (JNK) inhibition benefits pancreatic islet function and survival.
- Two JNK isoforms, JNK1 and JNK2, are present in the pancreas, with distinct roles.
- Understanding their specific roles is crucial for optimizing islet transplantation.
Purpose of the Study:
- To investigate the specific roles of JNK1 and JNK2 in experimental islet transplantation.
- To determine the impact of JNK isoform deficiency on islet function, survival, and transplant outcomes.
Main Methods:
- Utilized syngeneic islet transplantation models in wild-type, Jnk1(-/-), and Jnk2(-/-) mice.
- Assessed islet cell composition, function (insulin secretion), viability, cytokine production, and VEGF levels in vitro.
- Evaluated transplant outcomes in diabetic recipients.
Main Results:
- Jnk1(-/-) islets exhibited enhanced insulin secretion and resistance to cytokine-induced cell death compared to WT and Jnk2(-/-) islets.
- Jnk1(-/-) recipients showed accelerated diabetes reversal after WT islet transplantation, while Jnk2(-/-) recipients did not achieve reversal.
- Cytokine production by macrophages influenced islet graft outcomes.
Conclusions:
- JNK2 deficiency has a detrimental effect on islet graft outcomes, potentially due to compensatory JNK1 activation.
- Specific JNK1 blockade, rather than general JNK inhibition, may offer a superior therapeutic strategy for islet transplantation.
- Targeting JNK pathways holds promise for improving islet transplant efficacy.
Related Concept Videos
01:26Type I Diabetes II: Pathophysiology
01:20The JAK-STAT Signaling Pathway