Toll-like receptor-mediated responses of primary intestinal epithelial cells during the development of colitis

• Main Authors: Singh, J.C.I., Cruickshank, S.M., Newton, D.J., Wakenshaw, L., Graham, Anne M., Lan, J., Lodge, J.P.A., Felsburg, P.J., Carding, S.R.
• Language: en
• Published: The American Physiological Society 2009
• Subjects: Ulcerative colitis; Colon; Interleukin-2-deficient (IL-2¿/¿) mouse model; Colonic epithelial cells (CEC); Toll-like receptor (TLR)-mediated signaling
• Online Access: http://hdl.handle.net/10454/4048

no === The interleukin-2-deficient (IL-2¿/¿) mouse model of ulcerative colitis was used to test the hypothesis that colonic epithelial cells (CEC) directly respond to bacterial antigens and that alterations in Toll-like receptor (TLR)-mediated signaling may occur during the development of colitis. TLR expression and activation of TLR-mediated signaling pathways in primary CEC of healthy animals was compared with CEC in IL-2¿/¿ mice during the development of colitis. In healthy animals, CEC expressed functional TLR, and in response to the TLR4 ligand LPS, proliferated and secreted the cytokines IL-6 and monocyte chemoattractant protein-1 (MCP-1). However, the TLR-responsiveness of CEC in IL-2¿/¿ mice was different with decreased TLR4 responsiveness and augmented TLR2 responses that result in IL-6 and MCP-1 secretion. TLR signaling in CEC did not involve NF-B (p65) activation with the inhibitory p50 form of NF-B predominating in CEC in both the healthy and inflamed colon. Development of colitis was, however, associated with the activation of MAPK family members and upregulation of MyD88-independent signaling pathways characterized by increased caspase-1 activity and IL-18 production. These findings identify changes in TLR expression and signaling during the development of colitis that may contribute to changes in the host response to bacterial antigens seen in colitis.