The JNK Inhibitor XG-102 Protects against TNBS-Induced Colitis

Reinecke, Kirstin; Eminel, Sevgi; Dierck, Franziska; Roessner, W.; Kersting, S.; Chromik, Ansgar M.; Gavrilova, Olga; Laukevicience, Ale; Leuschner, Ivo; Waetzig, Vicki; Rosenstiel, Philip; Herdegen, Thomas; Sina, Christian

doi:10.1371/journal.pone.0030985

Cited by 45 publications

(30 citation statements)

References 71 publications

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“…D-JNKI-1 is produced by linking the 20 amino acid terminal JNK-inhibitory sequence (JNK binding domain) of JIP1/IB1 to a ten amino acid HIV-Tat transporter sequence for cell penetration 16–18. Peptidergic JNK inhibition using D-JNKI-1 has recently demonstrated preclinical and clinical benefit without undesirable side effects in several degenerative diseases such as traumatic hearing loss,17 colitis,19 uveitis,20 diabetes,21 myocardial ischemia,18 and ischemic stroke 13,14,22…”

Section: Introductionmentioning

confidence: 99%

The impact of JNK inhibitor D-JNKI-1 in a murine model of chronic colitis induced by dextran sulfate sodium

Kersting

Behrendt²,

Kersting³

et al. 2013

JIR

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Purpose:The c-Jun N-terminal kinases (JNK) are involved in the activation of T cells and the synthesis of proinflammatory cytokines. Several studies have established the relevance of the JNK pathway in inflammatory bowel diseases. The present study analyzed the therapeutic effect of D-JNKI-1, a specific JNK-inhibiting peptide, in a low-dose dextran sulfate sodium (DSS) model of chronic colitis.Methods:DSS colitis was induced in female C57/BL6 mice by cyclic administration using different concentrations of DSS (1.0% and 1.5%). Mice in the intervention groups received subcutaneous administration of 1 μg/kg D-JNKI-1 on days 2, 12, and 22. They were monitored daily to assess the severity of colitis, body weight, stool consistency, and the occurrence of occult blood or gross rectal bleeding using evaluation of the disease activity index. The animals were sacrificed after 30 days, and the inflamed intestine was histologically evaluated using a crypt damage score. Immunohistochemical quantification of CD4+ and CD8+ cells was also carried out.Results:Administration of 1 μg/kg D-JNKI-1 resulted in a significant decrease in the disease activity index (P = 0.013 for 1.0% DSS; P = 0.007 for 1.5% DSS). As a mild form of colitis was induced, histological examination did not show any distinct damage to the mucosa and crypts. However, expression of CD4+ and CD8+ cells was reduced in mice treated with D-JNKI-1 (not significant).Conclusion:Administration of D-JNKI-1 resulted in a clinical attenuation of chronic DSS colitis, and a therapeutic effect of D-JNKI-1 must therefore be assumed. The decrease in CD4+ and CD8+ cells may reflect the influence of D-JNKI-1 on T-cell activation, differentiation, and migration.

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Section: Introductionmentioning

confidence: 99%

The impact of JNK inhibitor D-JNKI-1 in a murine model of chronic colitis induced by dextran sulfate sodium

Kersting

Behrendt²,

Kersting³

et al. 2013

JIR

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“…58-60,[136][137][138][139][140][141] More recently, Ngoei et al identified the peptides L-PYC71N and D-PYC98 from a yeast twohybrid screen of a biodiverse gene fragment library 142,143. Both peptides are pan-JNK inhibitors…”

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confidence: 99%

Inhibitors of c-Jun N-Terminal Kinases: An Update

2014

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The c-Jun N-terminal kinases (JNKs) are serine/threonine kinases implicated in the pathogenesis of various diseases. Recent advances in the development of novel inhibitors of JNKs will be reviewed. Significant progress in the design of JNK inhibitors displaying selectivity versus other kinases has been achieved within the past 4 years. However, the development of isoform selective JNK inhibitors is still an open task.

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“…Mice harboring JNK1 or JNK2 inactivation exhibit opposite susceptibility to tumor formation induced by 12-0-tetradecanoyl-phorbol-13-acetate (7,38), and loss of JNK2 increases intestinal tumor susceptibility in Apc1638 ϩ/Ϫ mice with dietary modulation (3). JNK2 also regulates expression of proinflammatory cytokinesis in intestinal mucosa and is involved in the pathogenesis of inflammatory bowel diseases (8,32,42). Interestingly, JNKs were found to cross talk with Wnt/␤-catenin signaling in a variety of biological processes (33) and JNK2 interacts with and negatively regulates Wnt/␤-catenin signaling activity (15).…”

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confidence: 99%

Jnk2 deletion disrupts intestinal mucosal homeostasis and maturation by differentially modulating RNA-binding proteins HuR and CUGBP1

Chung

Rao

Zou

et al. 2014

American Journal of Physiology-Cell Physiology

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Homeostasis and maturation of the mammalian intestinal epithelium are preserved through strict regulation of cell proliferation, apoptosis, and differentiation, but the exact mechanism underlying this process remains largely unknown. c-Jun NH2-terminal kinase 2 (JNK2) is highly expressed in the intestinal mucosa, and its activation plays an important role in proliferation and also mediates apoptosis in cultured intestinal epithelial cells (IECs). Here, we investigated the in vivo function of JNK2 in the regulation of intestinal epithelial homeostasis and maturation by using a targeted gene deletion approach. Targeted deletion of the jnk2 gene increased cell proliferation within the crypts in the small intestine and disrupted mucosal maturation as indicated by decreases in the height of villi and the villus-to-crypt ratio. JNK2 deletion also decreased susceptibility of the intestinal epithelium to apoptosis. JNK2-deficient intestinal epithelium was associated with an increase in the level of the RNA-binding protein HuR and with a decrease in the abundance of CUG-binding protein 1 (CUGBP1). In studies in vitro, JNK2 silencing protected intestinal epithelial cell-6 (IEC-6) cells against apoptosis and this protection was prevented by inhibiting HuR. Ectopic overexpression of CUGBP1 repressed IEC-6 cell proliferation, whereas CUGBP1 silencing enhanced cell growth. These results indicate that JNK2 is essential for maintenance of normal intestinal epithelial homeostasis and maturation under biological conditions by differentially modulating HuR and CUGBP1.

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The JNK Inhibitor XG-102 Protects against TNBS-Induced Colitis

Cited by 45 publications

References 71 publications

The impact of JNK inhibitor D-JNKI-1 in a murine model of chronic colitis induced by dextran sulfate sodium

The impact of JNK inhibitor D-JNKI-1 in a murine model of chronic colitis induced by dextran sulfate sodium

Inhibitors of c-Jun N-Terminal Kinases: An Update

Jnk2 deletion disrupts intestinal mucosal homeostasis and maturation by differentially modulating RNA-binding proteins HuR and CUGBP1

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