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

Abstract

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.

IgG plasma cells initiate changes in the protein Csystem inmouse ulcerative colitis through CD14+CD64+ macrophage activation

“…Studies have shown that overactivation of MAPK is closely related with UC progression, and may represent a new target for antiinflammatory therapy. [33][34][35][36][37] Our study found compatible results: pP38 MAPK and pJNK MAPK expression were upregulated at the protein levels, while pERK MAPK expression was not changed, indicating that the change in EPCR was mediated by p38 MAPK and JNK MAPK.…”

c-Jun N-terminal kinase 2 promotes enterocyte survival and goblet cell differentiation in the inflamed intestine

“…However, none of our JNK knockout mice showed an improved colitis phenotype as it has been reported for the pan-JNK inhibitor SP600125 (refs 3,20,22 and the JNK1-specific inhibitor XG-102. 23,39 There might be four possible explanations that are not mutually exclusive: (i) Inhibitors may only partially block JNKs, thereby inhibiting proinflammatory effects while maintaining IEC cytoprotective functions. (ii) A total inhibition of all JNKs in immune cells may be required to constitute anti-inflammatory effects.…”

Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation

“…Although the role of intestinal epithelial MLCK in regulating mucosal permeability has been characterized extensively (Cunningham and Turner, 2012), participation of JNK1/2 in this process is less clear. Some have reported that deletion of JNK1 or JNK2 (or both) increases the susceptibility of mice in experimental models of colitis (Chromik et al, 2007;Kersting et al, 2013b); however, others have reported that selective inhibition of JNK1/2 is protective, reducing IEC apoptosis and modulating mucosal inflammatory mediator expression (Assi et al, 2006;Mitsuyama et al, 2006;Kersting et al, 2013a). Interestingly, in Crohn's disease patients, the expression of activated JNK is increased in the intestinal epithelium and mucosal immune cells (Bantel et al, 2002;Mitsuyama et al, 2006), and its selective inhibition reduces the expression of inflammatory mediators in colonic mucosal biopsies (Mitsuyama et al, 2006).…”