C-Jun N-terminal Kinase 2 Mediates Cytoprotective Functions in Intestinal Epithelial Cells and Ameliorates Experimental Colitis

Objective: C-Jun N-terminal kinases (JNKs) regulate several cellular functions including apoptosis, proliferation, differentiation and cytokine production. JNKs are encoded by three genes, but Jnk3 is not transcribed in the gastrointestinal tract. In this study we analysed the role of JNKs in the intestine using knockout mice.

Design: Complete deletion of JNKs in intestinal epithelial cells (IECs) was achieved by crossing mice with a conditional IEC-specific Jnk1 and a complete Jnk2 deletion (Jnk1^DIEC /Jnk2^-/-). We analysed these mice during homeostasis and dextran sodium sulfate (DSS)-induced colitis and compared their phenotype with wild-type (Wt) and single knockout animals (Jnk1^-/-, Jnk2^-/- and Jnk1^DIEC). Furthermore, we performed bone-marrow transfers to create chimeric Jnk2^-/- /Wt animals.

Results: In the colon JNK2 was more strongly expressed then JNK1 and highly induced upon inflammation. All untreated mice were healthy, developed normally and did not show any signs of intestinal inflammation or barrier dysfunctions. However, Jnk1^DIEC /Jnk2^-/- and to a lesser extent Jnk2^-/- mice showed enhanced IEC cell turnover with increased rates of apoptosis and proliferation. Jnk1 deficiency alone had only a minor effect on IEC cell turnover. After DSS challenge Jnk2^-/- mice exhibited increased pathology, IEC apoptosis, goblet cells loss, inflammation, ER stress and barrier dysfunction. Investigation of chimeric Jnk2^-/- /Wt mice showed that JNK2 expression in non-hematopoietic cells mediated the protective effects. Jnk1 deficiency alone or in combination with Jnk2deletion showed only a slightly aggravated colitis.

Conclusion: JNKs, and in particular JNK2, have cytoprotective functions in IECs and ameliorate chemical induced acute colitis