6533b871fe1ef96bd12d2594

RESEARCH PRODUCT

Knock out der c-Jun N-terminalen Kinase 2 (JNK2) aggraviert die Entwicklung der chronischen DSS-Colitis unabhängig von der intestinalen Zytokin-Expression

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Background The c-Jun N-terminal kinase 2 (JNK2) is involved in signal transduction of inflammatory bowel diseases (IBD) and regulates the expression of pro-inflammatory cytokines. For this reason, JNK2 is considered as novel target for IBD therapy. The aim of this study was 1.) to examine the function of JNK2 applying a low dose Dextran Sulfate Sodium (DSS) model of chronic experimental colitis in JNK2 knock out mice and 2.) to analyze the expression of JNK2 dependent cytokines. Material and Methods: For induction of a mild chronic colitis, female JNK2 knockout mice (JNK2 ko) and their wildtype controls (WT2) received three cycles of DSS treatment, each consisting of 1.0 % DSS for 5 days, followed by 5 days with water. Control groups of both genotypes received water only (each n = 9). Animals were daily evaluated by a disease activity index (DAI). After 30 days all animals were sacrificed, and the inflamed intestine was histologically evaluated by a crypt damage score (CDS). Analysis of TNFα, IL-6 and TGFβ expression in the colon was carried out using LightCycler® real-time PCR with calibrator-normalized quantification. Statistical analysis was carried out by ANOVA. P-values ≤ 0.05 were considered statistically significant. Results: In WT2 animals, application of 1.0 % DSS did not induce a chronic colitis reflected by a mean DAI of 1.14 (± 0.38) which was not significantly elevated compared to 0.58 (± 0.15) in the H2O control group. In contrast, DSS application in JNK2 ko animals resulted in a chronic colitis with a mean DAI of 2.32 (± 0.28) which was significantly higher compared to the H2O control group with 0.61 (± 0.15) (p ≤ 0.001) and compared to the WT2-DSS group (p ≤ 0.05). The calibrator normalized quantitative real-time PCR did not show any significant differences between the four experimental groups regarding the expression of TNFα, IL-6 and TGFβ. Conclusion: DSS application in a definite concentration (1.0 %), which is unable to induce colitis in wildtype animals, leads to a clinically and histologically detectable chronic colitis in JNK2 ko mice. It remains to be elucidated how inactivation of JNK2 aggravates DSS colitis. However, the JNK2 dependent expression of TNFα, IL-6 and TGFβ does not play a major role. We hypothesize that the functional deletion of the otherwise pro-apoptotic JNK2 prolongs the activity of pro-inflammatory immune cells leading to a perpetuation of the inflammation. Thus inhibition of JNK2 does not represent a reasonable principal in IBD therapy.