Lala, S.G.; Ogura, Y.; Hor, S.K.; Abeya, M.; Osborne, C.; Davies, S.; Ogunbiyi, O.; Nunez, G.; Keshav, S.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA39
Academic Journal
Background and Aims: Mutations in the NOD2 gene predisposing to Crohn's disease (CD) are predominantly associated with terminal ileal disease. The mechanisms by which these mutations cause ileitis are unknown, as NOD2 is most highly expressed by circulating peripheral blood monocytes, which are ubiquitously distributed throughout the body. Paneth cells are specialised intestinal epithelial cells critically important in enteric antibacterial defence, which respond to bacterial lipopolysaccharide (LPS) through undefined pathways. They are also most numerous in the terminal ileum, and we therefore determined if Paneth cells as well as tissue macrophages in the terminal ileum expressed the NOD2 gene. Methods: In situ hybridisation and immunohistochemistry were used to determine RNA and protein expression in tissue sections, and quantitative real time RT-PCR was used to measure gene expression in intestinal epithelial cell lines and peripheral blood mononuclear cells. Results: Paneth cells and monocytes express NOD2 mRNA and protein in CD affected and normal terminal ileum. In Crohn's ileitis, monocytes but not macrophages located within the lamina propria and granulomas, express NOD2 protein and RNA. Paneth cells, monocytes, and tissue macrophages also express tumour necrosis factor alpha (TNFα) mRNA in CD. In vitro, a decrease in NOD2 expression is seen in monocytes differentiating into macrophages. Caco-2 cells, which display some features of Paneth cell differentiation, constitutively express more NOD2 mRNA than monocyte derived macrophages. Conclusions: NOD2 expressing-Paneth cells could play a critical and hitherto unrecognised role in the pathogenesis of terminal ileal CD, while the role of the NOD2 gene in mononuclear cells probably depends critically on their differentiation state.


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