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

Abstract

c-Jun N-terminal kinases (JNKs) contribute to immune signaling but their functional role during intestinal mucosal inflammation has remained ill defined. Using genetic mouse models, we characterized the role of JNK1 and JNK2 during homeostasis and acute colitis. Epithelial apoptosis, regeneration, differentiation, and barrier function were analyzed in intestinal epithelium-specific (ΔIEC) or complete JNK1 and bone marrow chimeric or complete JNK2 deficient mice as well as double-knockout animals (JNK1JNK2) during homeostasis and acute dextran sulfate sodium (DSS)-induced colitis. Results were confirmed using human HT-29 cells and wild-type or JNK2-deficient mouse intestinal organoid cultures. We show that nonhematopoietic JNK2 but not JNK1 expression confers protection from DSS-induced intestinal inflammation reducing epithelial barrier dysfunction and enterocyte apoptosis. JNK2 additionally enhanced Atonal homolog 1 expression, goblet cell and enteroendocrine cell differentiation, and mucus production under inflammatory conditions. Our results identify a protective role of epithelial JNK2 signaling to maintain mucosal barrier function, epithelial cell integrity, and mucus layer production in the event of inflammatory tissue damage.

The lipid peroxidation product EKODE exacerbates colonic inflammation and colon tumorigenesis

“…Previous studies showed that treatment with JNK inhibitors (e.g. SP600125) attenuated DSS-induced colitis in rodent models [ [28] , [29] , [30] ] and play critical roles in regulating colon homeostasis [ 31 ], however, genetic ablation of JNK1 or JNK2 increased DSS-induced colitis in mice [ [32] , [33] , [34] ]. Regarding its roles in CRC, JNK overexpression exacerbated AOM/DSS-induced CRC, but had little impact on tumorigenesis triggered by Apc mutation [ 35 ].…”

ATF2 and ATF7 Are Critical Mediators of Intestinal Epithelial Repair

“…In intestinal homeostasis, inflammation, and cancer, the critical function of c-Jun has been studied extensively. [8][9][10][11][12][13] ATF2 is one of the potential heterodimer partners of c-Jun and is known to be regulated by pathways that play a critical role in the intestinal epithelium such as the Wnt and bone morphogenetic protein pathways. [14][15][16][17][18] Moreover, ATF2 contains an N-terminal activation domain that, as for c-Jun, can be activated by several mitogen-activated protein kinases (MAPKs), which have been implicated to play an important role in immune maintenance, hence regulating immune responses.…”

Combination of arsenic trioxide and Dasatinib: a new strategy to treat Philadelphia chromosome‐positive acute lymphoblastic leukaemia

“…JNK1 and JNK2 are widely expressed, while JNK3′s expression is predominantly restricted to the brain, heart and testis. Studies suggest that the activation of JNK1 may induce apoptosis, whereas JNK2 inhibits it . At least four alternatively spliced transcript variants of JNK1 exist, including two short JNK1 isoforms (JNK1‐a1 and JNK1‐b1) and two long JNK1 isoforms (JNK1‐a2 and JNK1‐b2).…”

“…19]. At least four alternatively spliced transcript variants of JNK1 exist, including two short JNK1 isoforms (JNK1-a1 and JNK1-b1) and two long JNK1 isoforms (JNK1-a2 and JNK1-b2).…”