Cux1 Transcription Factor Is Induced in Inflammatory Bowel Disease and Protects Against Experimental Colitis

Background: Cux1 is a ubiquitous transcriptional factor that has been associated with cell proliferation, migration, invasion, and differentiation. Cux1 is an effector of the transforming growth factor beta (TGF beta) pathway, PAR2 receptor signaling, and cellular migration, mechanisms intimately related to inflammatory bowel diseases (IBD). Methods: CD1 mice treated with dextran sulfate sodium (DSS) in drinking water and cultured intestinal epithelial cells were used to determine Cux1 expression under inflammatory conditions. A commercial cDNA library was used to monitor CUX1 expression in IBD patients. The Cux1(Delta HD/Delta HD) hypomorphic mouse model (Cux1 Delta HD) treated with DSS in drinking water was used and the disease severity assessed. Results: Cux1 expression increased in cultured intestinal epithelial cells stimulated with tumor necrosis factor alpha (TNF alpha), in the mouse intestinal epithelium during experimental colitis and in human IBD patient samples. DSS-induced colitis in Cux1 Delta HD mice was more severe according to clinical observations such as weight loss, colon length, and rectal bleeding. Histological observations confirmed an increase of IBD-related morphological changes including ulceration and mucosal infiltration of leukocytes in Cux1 Delta HD mice. An increased number of pSer 276 -RelA-positive cells and higher expression levels of proinflammatory cytokines were also measured in the colon of Cux1 Delta HD diseased animals. Elevated levels of Cxcl1 were measured before and after DSS-treatment and a greater neutrophilic infiltration was quantified in DSS-treated Cux1 Delta HD mice. Finally, mucosal healing was significantly impaired in Cux1 Delta HD mice during recovery from DSS treatment. Conclusions: CUX1 is increased in response to inflammatory stress and its nuclear expression is crucial to protect against DSS-induced colitis and subsequent mucosal healing.