MODULATING TOLL-LIKE RECEPTOR 4 SIGNALING PATHWAY PROTECTS MICE FROM EXPERIMENTAL COLITIS

Abstract

Background/Aim: Several reports have indicated that environmental factors and defects in innate immunity are central to the pathogenesis of inflammatory bowel disease (IBD). Although bacteria producing lipopolysaccharide (LPS), which is a Toll-like receptor (TLR) 4 agonist, play a crucial role in the development of experimental colitis, LPS tolerance following initial exposure to LPS can result in a state of hyporesponsiveness to subsequent LPS challenge. Therefore, we initiated this study to explore the role of LPS tolerance in the development of colitis. Methods: Dextran sulfate sodium (DSS) colitis was induced in Balb/c mice with or without daily intraperitoneal administration of LPS. Disease activity and cytokine mRNA expression in the colon were evaluated. To confirm LPS tolerance, mouse conventional bone marrow-derived dendritic cells (BMDC) were preincubated with or without LPS, and were restimulated with LPS 24 h after first exposure. Cytokine production was measured by ELISA, and mRNA expression was evaluated by RT-PCR. Furthermore, we investigated the expression of negative regulators of LPS tolerance in BMDC. Results: Administration of LPS significantly suppressed colonic inflammation of DSS-induced colitis. After subsequent stimulation with LPS, TNF-α production was reduced in BMDC. IRAK-M, a negative regulator of TLR4 signaling, mRNA expression was up-regulated in LPS-treated BMDC. Conclusion: LPS tolerance was able to protect mice from DSS-induced colitis, and IRAK-M participated in this tolerance. Taken together, these observations suggest that loss of exposure to LPS is involved in the pathogenesis of IBD.