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Published on: November 9, 2018
Genetic deletion of JNK1 and JNK2 aggravates the DSS-induced colitis in mice
A M Chromik1, A M Müller, J Körner
1Department of General and Visceral Surgery, St. Josef Hospital, Ruhr-University of Bochum, Bochum, Germany. a.chromik@klinikum-bochum.de
Abstract:
The c-Jun N-terminal kinases (JNKs) are considered as novel targets for therapy of inflammatory bowel diseases (IBD). However, the relevant JNK isoforms have to be elucidated. Here, we analyze the individual contribution of the JNK1 and JNK2 isoforms in a dextran sulfate sodium (DSS) model of experimental colitis. JNK1 and JNK2 knockout mice (JNK1 ko, JNK2 ko) and their wild-type controls (WT1, WT2) received three cycles of DSS treatment, each consisting of 1.7% DSS for 5 days, followed by 5 days with water. Animals were daily evaluated by a disease activity index (DAI) comprising measurement of body weight, estimation of stool consistency, and test for occult blood/gross rectal bleeding. After 30 days all animals were sacrificed, and the inflamed intestine was histologically evaluated by a crypt damage score. Unexpectedly, neither JNK1 ko nor JNK2 ko prevented mice from developing a chronic colitis when compared to wild-type controls WT1 and WT2, respectively. On the contrary, DAI and mortality were aggravated in JNK2 ko compared to WT2. DAI and mortality did not differ between JNK1 ko and WT1, but the histological crypt damage score was significantly enhanced in the cecum of JNK1 ko mice. Genetic deletion of JNK2 worsens the disease outcome in an experimental model of murine colitis. We hypothesize that the functional deletion of the otherwise proapoptotic JNK2 prolongs the activity of proinflammatory immune cells with deterioration of disease activity.
Insights
The study investigated c-Jun N-terminal kinases (JNKs) in inflammatory bowel disease (IBD) models. Deleting JNK2 worsened colitis in mice, suggesting JNK2 plays a protective role against IBD progression.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- C-Jun N-terminal kinases (JNKs) are implicated as therapeutic targets for inflammatory bowel diseases (IBD).
- Elucidating the specific roles of JNK isoforms, JNK1 and JNK2, is crucial for targeted IBD therapies.
Purpose of the Study:
- To investigate the individual contributions of JNK1 and JNK2 isoforms in a dextran sulfate sodium (DSS)-induced experimental colitis model.
- To determine the impact of JNK1 and JNK2 deficiency on disease activity and intestinal damage in mice.
Main Methods:
- JNK1 and JNK2 knockout mice, along with wild-type controls, were subjected to three cycles of DSS treatment.
- Disease activity was assessed daily using a disease activity index (DAI), including body weight, stool consistency, and rectal bleeding.
- Histological evaluation of intestinal tissue, specifically a crypt damage score, was performed post-sacrifice.
Main Results:
- Neither JNK1 nor JNK2 knockout mice were protected from developing chronic colitis compared to wild-type controls.
- JNK2 knockout mice exhibited aggravated disease activity index (DAI) and increased mortality compared to wild-type controls.
- While DAI and mortality were similar between JNK1 knockout and wild-type mice, JNK1 knockout mice showed significantly enhanced histological crypt damage in the cecum.
Conclusions:
- Genetic deletion of JNK2 exacerbates disease outcomes in a murine model of experimental colitis.
- The findings suggest that JNK2 may possess a protective role, potentially by regulating the pro-inflammatory immune cell activity and apoptosis.
- Further research into JNK isoform-specific functions is warranted for developing effective IBD therapeutics.
