Our best knowledge, this is the first study that showed a down-regulation of the gene and protein expression of CFTR or ABCC7 in patients with active UC compared to UC in remission and normal controls without inflammation. It is important to note that low CFTR gene expression was significant associated with young age at diagnosis (< 40 years old) and a clinical course characterized by persistent UC activity.
It is well known that CFTR has been widely studied in cystic fibrosis (CF) and recently, it has grown interest in to study its role in other diseases or inflammatory conditions such as in the biliary epithelium and intestine 12,22−24. In animal models and in vitro studies have demonstrated the role of CFTR in the intestinal inflammatory process characterized by histological infiltration of immune cells and increased of inflammatory fecal biomarkers13–16 .
Our findings are similar to that reported by Werlin et al. and Lee et al. who found increased levels of fecal calprotectin in children with CF13,15. In vitro studies have demonstrated that a down-regulation of CFTR is contributing to chronic inflammation as we found in patients with active UC. This could be explained by findings reported by Wang et al who reported the effect of mutant ABCC7/CFTR in bronchial epithelial cell line (CFBE cells) during TNFα recombinant stimulation, they observed that ABCC7/CFTR mutant increase the activity of transcriptional nuclear factor ĸB (NF-ĸB) and production of pro-inflammatory cytokines compared to those with normal function of CFTR17.
Similar findings by Defu Li et al. who found increase in the NF-ĸB activity, IL-8 and IL-6 production in human bronchial epithelial cells (16HBE) that had a down-regulation of ABCC7/CFTR18 as well as in patients with human lung adenocarcinoma cell lines25. In other cell lines from colorectal carcinoma, Crites K et al reported that a down-regulation of ABCC7/CFTR increased the production of IL-6, IL-1β and IL-8 in CACO2 and HT29 cells due to the activation of ERK1/2, MAPK, IΚBα and NF-ĸB pathways26. In a knock-out animal model of ABCC7/CFTR, they found that the down regulation of CFTR produced inflammation through the increased of NF-ĸB, TNFα and IL-6 in the mouse intestine, CACO2 cells and colangiocytes stimulated by lipopolysaccharides from Escherichia coli 2326, 27. In other study performed in rats and 16HBE140 cells found that down-regulation of CFTR increased the production of IL-8 compared to those that overexpressed CFTR with lack of MAPK/NF-ĸB activation19 and the same finding was also observed in mutant CFTR (DF508) mice and HaCaT cells that the down-regulation of the CFTR expression exhibited inflammation and delayed cutaneous wound healing28.
Our findings are similar to above mentioned studies confirming the role of down-regulation of CFTR in the development of inflammatory process in patients with active UC.
Nevertheless, it already known that CFTR interacts with a variety of proteins and regulates its function10. Recent studies have demonstrated in Cftr knock-out mice model higher levels of IL-17 compared to wild type mouse during infection with Pseudomonas aeruginosa and resulting in the perpetuation of inflammatory process by neutrophil recruitment suggesting that the absence of CFTR contributes to the inflammation by IL17 production29 and have been also observed in patients with active UC30.
The CFTR is a channel expressed in the intestine that regulates the efflux of chloride and bicarbonate ions and also participates actively in the pH regulation9,10. A proposed hypothesis explaining the role of CFTR in UC patients is that down-regulation of CFTR affects the pH balance in the colon producing a decreased expression of MUC11 and MUC12 contributing to the adherence of bacteria and promoting the colonic inflammation 10,11,31 and it was reported by our group a decreased gene expression of MUC20 in patients with active UC compared to UC remission and normal controls 32.
On the other hand, changes in the intestinal pH and decreased MUC11 and MUC12 expression promotes the colonization of phatobiontic microbiota in the intestinal lumen as it has been reported in IBD patients11,23,33. Phatobiontic microbiota increased the expression, recognition and activation of TLR4 with activation of NF-ĸB and subsequent production of pro-inflammatory cytokines such as IL-6 and IL-8.23,26,27,33,34 Microbiota dysbiosis is associated with reduction of short-chain fatty acids, an anti-inflammatory molecules that regulates the immune response in the intestine, this fatty acids ameliorates the intestinal inflammation in IBD in animal model. 35 But, is possible that down-regulation of ABCC7/CFTR contribute to IL17 up-regulation in patients with UC allowing the persistent activity as we observed in the active group in our study.29,30