title: Toll-like receptor-mediated responses of primary intestinal epithelial cells during the development of colitis.
abstract: 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-kappaB (p65) activation with the inhibitory p50 form of NF-kappaB 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.
authors.affiliation: School of Biochemistry and Microbiology, The University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Joy Carmelina Indira
authors.initials: JC
authors.lastname: Singh
authors.forename: Sheena Margaret
authors.initials: SM
authors.lastname: Cruickshank
authors.forename: Darren James
authors.initials: DJ
authors.lastname: Newton
authors.forename: Louise
authors.initials: L
authors.lastname: Wakenshaw
authors.forename: Anne
authors.initials: A
authors.lastname: Graham
authors.forename: Jinggang
authors.initials: J
authors.lastname: Lan
authors.forename: Jeremy Peter Alan
authors.initials: JP
authors.lastname: Lodge
authors.forename: Peter John
authors.initials: PJ
authors.lastname: Felsburg
authors.forename: Simon Richard
authors.initials: SR
authors.lastname: Carding
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D001419:Bacteria / Q000378:metabolism; D015153:Blotting, Western; D020170:Caspase 1 / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D003092:Colitis / Q000473:pathology*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000473:pathology*; D005434:Flow Cytometry; D020382:Interleukin-18 / Q000096:biosynthesis; D007422:Intestines / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015854:Up-Regulation / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D018076:DNA, Complementary; D020382:Interleukin-18; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D020170:Caspase 1