Modulating Toll-like receptor 4 signaling pathway protects mice from experimental colitis

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.

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.

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.

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.