Abstract
Oxidative stress plays an important role in the pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease (CrD). High levels of Reactive Oxygen Species (ROS) induce the activation of the redox-sensitive nuclear transcription factor kappa-B (NF-κB), which in turn triggers the inflammatory mediators. Butyrate decreases pro-inflammatory cytokine expression by the lamina propria mononuclear cells in CrD patients via inhibition of NF-κB activation, but how it reduces inflammation is still unclear. We suggest that butyrate controls ROS mediated NF-κB activation and thus mucosal inflammation in intestinal epithelial cells and in CrD colonic mucosa by triggering intracellular antioxidant defense systems. Intestinal epithelial Caco-2 cells and colonic mucosa from 14 patients with CrD and 12 controls were challenged with or without lipopolysaccaride from Escherichia Coli (EC-LPS) in presence or absence of butyrate for 4 and 24 h. The effects of butyrate on oxidative stress, p42/44 MAP kinase phosphorylation, p65-NF-κB activation and mucosal inflammation were investigated by real time PCR, western blot and confocal microscopy. Our results suggest that EC-LPS challenge induces a decrease in Gluthation-S-Transferase-alpha (GSTA1/A2) mRNA levels, protein expression and catalytic activity; enhanced levels of ROS induced by EC-LPS challenge mediates p65-NF-κB activation and inflammatory response in Caco-2 cells and in CrD colonic mucosa. Furthermore butyrate treatment was seen to restore GSTA1/A2 mRNA levels, protein expression and catalytic activity and to control NF-κB activation, COX-2, ICAM-1 and the release of pro-inflammatory cytokine. In conclusion, butyrate rescues the redox machinery and controls the intracellular ROS balance thus switching off EC-LPS induced inflammatory response in intestinal epithelial cells and in CrD colonic mucosa.
Highlights
Intestinal epithelial cells constitute the interface between the gut lumen and the innate and adaptive immune system [1]
We demonstrated that butyrate prevents LPS-induced decrease of GSTA1/A2 mRNA, protein and activity in LPS-stimulated intestinal epithelial cells (Figure 1A and B and Figure S1A)
Using a well established tissue culture model for biopsy of human Crohn’s Disease (CrD) colonic mucosa [28], we showed that butyrate prevents LPS-induced decrease of GSTA1/A2 mRNA, protein and activity in LPS-treated colonic mucosa in CrD patients (Figure 1C and D and Figure S1C)
Summary
Intestinal epithelial cells constitute the interface between the gut lumen and the innate and adaptive immune system [1]. IBD is characterized by the loss of tolerance in the intestinal immune system towards the intestinal microbiota resulting in constant immune activation which leads to mucosal tissue damage and chronic inflammation [3]. These spontaneously relapsing chronic intestinal inflammations are subdivided into two main idiopathic pathologies ulcerative colitis (UC) and Crohn’s Disease (CrD). High ROS levels have been reported to promote activation and translocation of NF-kB [9] into the nucleus through alternative phosphorylation of Ik-B-a which leads to its ubiquitynation and degradation [9]. This ROS/NF-kB self-sustaining regulatory loop may contribute to the perpetuation and exacerbation of chronic inflammation [10]
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