Disruption of the<i>Jnk2 (Mapk9)</i>gene reduces destructive insulitis and diabetes in a mouse model of type I diabetes

Jaeschke, Anja; Rincón, Mercedes; Doran, Beth; Reilly, Judith; Neuberg, Donna; Greiner, Dale L.; Shultz, Leonard D.; Rossini, Aldo A.; Flavell, Richard A.; Davis, Roger J.

doi:10.1073/pnas.0502143102

Cited by 82 publications

(76 citation statements)

References 32 publications

(26 reference statements)

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“…Notably, whereas isolated Jnk2 deficiency had no impact on diet-induced obesity and insulin resistance, it protected animals against type 1 diabetes and atherosclerosis (25,26). We observed a small but statistically significant reduction in plasma cholesterol, which may contribute to the atheroprotective effect of JNK2 deficiency.…”

Section: Jnk Activity and Inflammatory Cytokine Expression In Mutantmentioning

confidence: 62%

“…Isolated JNK1 but not JNK2 deficiency results in reduced adiposity and increased insulin sensitivity in mouse models of obesity (10). Interestingly, however, JNK2 but not JNK1 deficiency was reported to provide protection against atherosclerosis and type 1 diabetes in mice (25,26). Because JNK isoforms can influence each other's activities (27), part of this subtype specificity might be related to the action of each JNK isoform in the relevant target tissue.…”

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confidence: 99%

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Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance

Tuncman

Hirosumi

Solinas

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

320

262

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The c-Jun N-terminal kinases (JNKs) are key regulators of inflammation and interfere with insulin action in cultured cells and whole animals. Obesity increases total JNK activity, and JNK1, but not JNK2, deficiency results in reduced adiposity and improved insulin sensitivity. Interestingly, a higher-than-normal level of JNK activation is observed in Jnk2 ؊/؊ mice, particularly in the liver, indicating an interaction between the isoforms that might have masked the metabolic activity of JNK2 in isolated mutant mice. To address the role of the JNK2 isoform in metabolic homeostasis, we intercrossed Jnk1 ؊/؊ and Jnk2 ؊/؊ mice and examined body weight and glucose metabolism in the resulting mutant allele combinations. Among all of the viable genotypes examined, we observed only reduced body weight and increased insulin sensitivity in Jnk1 ؊/؊ and Jnk1 ؉/؊ Jnk2 ؊/؊ mice. These two groups of mice also exhibited reduced total JNK activity and cytokine expression in liver tissue compared with all other genotypes examined. These data indicate that the JNK2 isoform is also involved in metabolic regulation, but its function is not obvious when JNK1 is fully expressed because of regulatory crosstalk between the two isoforms.diabetes ͉ fatty liver ͉ metabolic syndrome ͉ inflammation ͉ stress

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Section: Jnk Activity and Inflammatory Cytokine Expression In Mutantmentioning

confidence: 62%

mentioning

confidence: 99%

Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance

Tuncman

Hirosumi

Solinas

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

320

262

View full text Add to dashboard Cite

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“…Inhibition of JNK activation protects beta cell lines against IL-1β-induced apoptosis [5,12] and human islets against the destruction mediated by IL-1β, TNF-α and IFN-γ [13,14]. Disruption of JNK activation also protects beta cells against T-cell-mediated killing [15], increases islet survival after isolation [13,16] and improves islet graft function [16,17]. Taken together, these observations demonstrate that JNK inhibition is crucial in maintaining the function and survival of beta cells when exposed to multiple stressors.…”

Section: Introductionmentioning

confidence: 99%

Growth arrest- and DNA-damage-inducible 45β gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1β-induced apoptosis in insulin-producing INS-1E cells

et al. 2006

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Aims/hypothesis: IL-1β is a candidate mediator of apoptotic beta cell destruction, a process that leads to type 1 diabetes and progression of type 2 diabetes. IL-1β activates beta cell c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38, all of which are members of the mitogen-activated protein kinase (MAPK) family. Inhibition of JNK prevents IL-1β-mediated beta cell destruction. In mouse embryo fibroblasts and 3DO T cells, overexpression of the gene encoding growth arrest and DNA-damage-inducible 45β (Gadd45b) downregulates pro-apoptotic JNK signalling. The aim of this study was to investigate if Gadd45b prevents IL-1β-induced beta cell MAPK signalling and apoptosis. Materials: Rat insulinoma INS-1E cells and mouse beta-TC3 cells stably expressing Gadd45b were generated. The effects of Gadd45b expression on signalling by JNK, ERK and p38 were assessed by Western blotting and kinase assays. Apoptosis rate was measured by terminal deoxynucleotidyl-mediated dUTP-biotin nick end-labelling (TUNEL) and an ELISA designed to detect apoptotic nucleosomes. Expression of endogenous Gadd45b mRNA was measured by RT-PCR. Results: In INS-1E and beta-TC3 cells, expression ofGadd45b inhibited IL-1β-induced activation of JNK and ERK, but augmented IL-1β-mediated p38 activity. IL-1β-induced nitric oxide production and decreases in insulin content and secretion were reduced by GADD45β. IL-1β-induced apoptosis was reduced by GADD45β by up to 77%. Although IL-1β stimulated the time-dependent induction of endogenous Gadd45b in INS-1E cells and rat islets, expression levels were lower in these cells than in IL-1β-exposed NIH-3T3 and 3DO T cells.

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“…Three different isoforms of JNK (JNK1, 2 and 3) have been identified; JNK1 and JNK2 are widely produced, while JNK3 production is restricted to the brain [12]. In diabetes, JNK1 plays a very important role in obesity-induced insulin resistance [13], and JNK2 contributes to insulitis in NOD mice [14]. Furthermore, JNK1/2 co-inhibition prevents effector T cell function [15].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2008

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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 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.

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Disruption of theJnk2 (Mapk9)gene reduces destructive insulitis and diabetes in a mouse model of type I diabetes

Cited by 82 publications

References 32 publications

Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance

Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance

Growth arrest- and DNA-damage-inducible 45β gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1β-induced apoptosis in insulin-producing INS-1E cells

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

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