203 Mesenchymal Stem Cell Transplantation Improves Chronic Colitis-Associated Cholangitis Through Inhibiting the Activity of LPS/TLR4

Abstract

Background: The hepatobiliary manifestation, cholangitis, is frequently encountered in inflammatory bowel disease (IBD). Toll receptor 4 (TLR4) signaling pathway plays a pivotal role in the pathogenesis of various chronic liver diseases. Mesenchymal stem cells (MSCs) are important means for the treatment of IBD and liver diseases. This study investigated the protective role andmechanism of MSCs in the chronic colitis-associated cholangitis. Methods: Mouse chronic colitis model was established by administration of dextran sodium sulfate (DSS) drinking water and treated with MSCs. Mice were grouped as follows: DSS+Vehicle group (n=10), DSS+MSCs group (n=10) and control group (n=10). Severity of colitis was evaluated by disease activity index (DAI), body weight (BW), colon length, histopathology. Histology and function of mouse liver were checked correspondingly. Serum LPS levels and bacterial translocation of mesenteric lymph nodes were detected. Pro-inflammatory cytokines including TNF-α, IFN-γ, IL-1β, IL-17A, TLR4, TRAF6, and NF-κBwere detected by immunohistochemical staining, western blot analysis and real-time PCR, respectively. Results: DSSinduced chronic colitis model was characterized by reduced BW, higher DAI, worsened histologic inflammation, and enhanced levels of LPS and bacterial translocation. Chronic colitis-associated hepatobiliary complications revealed histomorphological signs of cholangitis and the impaired liver function. The more severer the degree of colitis showed, the more severer cholangitis were showed. The protein and mRNA levels of TNFα, IFN-γ, IL1β, IL-17A, TLR4, TRAF6 and NF-κB significantly increased after DSS administration. MSCs transplantation markedly ameliorated the pathology of colon and liver by reduction of LPS level, and proteins and mRNA expressions of TNF-α, IFN-γ, IL-1β, IL-17A, TLR4, TRAF6 and NF-κB as well. Conclusions: Our results reveal that MSCs may be a novel therapeutic drug for the treatment of chronic colitis-associated cholangitis, which correlated to downregulating the LPS/TLR4 signaling pathway.