title: Nod2 improves barrier function of intestinal epithelial cells via enhancement of TLR responses.
abstract: Intestinal epithelial cells (IECs) form a physical barrier between the internal milieu and the intestinal microflora via the expression of tight junctions. TLR-mediated recognition of intestinal microflora by IECs is important for tight junction preservation, production of chemokines, and cell survival. Disturbance of the IEC barrier function results in bacterial invasion and contributes to the development of inflammatory bowel disease. We observed that muramyl dipeptide (MDP), a breakdown product of bacterial peptidoglycan, strongly enhances subsequent Toll-like receptor (TLR) responses in murine colonic epithelium cell lines. Prior exposure to MDP significantly increased the production of chemokines and cytokines and improved the barrier function induced by different TLR2 and TLR4 ligands. shRNA knock-down studies showed that MDP recognition by Nod2 mediated the enhancement of TLR responses. Our studies indicate that Nod2 stimulation by MDP significantly enhances TLR-mediated IEC barrier function and chemokine production. Failure of this protective mechanism may contribute to the increased risk of Crohn's disease in individuals with a loss-of-function mutation in NOD2.
authors: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.
authors: Ida H
authors: IH
authors: Hiemstra
authors: Gerd
authors: G
authors: Bouma
authors: Dirk
authors: D
authors: Geerts
authors: Georg
authors: G
authors: Kraal
authors: Joke M M
authors: JM
authors: den Haan
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004847:Epithelial Cells / Q000378:metabolism / Q000648:ultrastructure; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism*; D007422:Intestines / Q000276:immunology; D051379:Mice; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D019108:Tight Junctions / Q000648:ultrastructure; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D018925:Chemokines; D016207:Cytokines; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D034741:RNA, Small Interfering; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000119:Acetylmuramyl-Alanyl-Isoglutamine