Abstract
Resident human lamina propria immune cells serve as powerful effectors in host defense. Molecular events associated with the initiation of an intestinal inflammatory response in these cells are largely unknown. Here, we aimed to characterize phenotypic and functional changes induced in these cells at the onset of intestinal inflammation using a human intestinal organ culture model. In this model, healthy human colonic mucosa was depleted of epithelial cells by EDTA treatment. Following loss of the epithelial layer, expression of the inflammatory mediators IL1B, IL6, IL8, IL23A, TNFA, CXCL2, and the surface receptors CD14, TLR2, CD86, CD54 was rapidly induced in resident lamina propria cells in situ as determined by qRT-PCR and immunohistology. Gene microarray analysis of lamina propria cells obtained by laser-capture microdissection provided an overview of global changes in gene expression occurring during the initiation of an intestinal inflammatory response in these cells. Bioinformatic analysis gave insight into signalling pathways mediating this inflammatory response. Furthermore, comparison with published microarray datasets of inflamed mucosa in vivo (ulcerative colitis) revealed a significant overlap of differentially regulated genes underlining the in vivo relevance of the organ culture model. Furthermore, genes never been previously associated with intestinal inflammation were identified using this model. The organ culture model characterized may be useful to study molecular mechanisms underlying the initiation of an intestinal inflammatory response in normal mucosa as well as potential alterations of this response in inflammatory bowel disease.
Highlights
Investigations aimed at understanding molecular events underlying intestinal inflammation are largely focused on chronic processes, summarized as inflammatory bowel diseases (IBD)
Healthy colonic mucosa of defined size was prepared from freshly obtained human surgical specimens and depleted of epithelial cells by exposure to ethylenediaminetetraacetic acid (EDTA) under standardized conditions
In the human intestinal mucosa, molecular processes determining the onset of an inflammatory response in resident lamina propria cells are as yet largely unknown
Summary
Investigations aimed at understanding molecular events underlying intestinal inflammation are largely focused on chronic processes, summarized as inflammatory bowel diseases (IBD). Such studies are mostly performed in symptomatic, i.e. ongoing pathological situations: in the murine system following treatment with artificial agents such as dextran sulfate (DSS) [1]; in humans, tissues derived from inflamed intestine in Crohn’s disease, ulcerative colitis etc. That so far only symptomatic disease situations have been studied, it seems not surprising that all established therapies to treat IBD are of symptomatic nature [2,3]. Virtually nothing is known concerning the conditions driving intestinal inflammation at its very onset. The central and obvious question, namely, how resident immune effector cells of the intestine differentiate from their physiologic quiescent stages into activated, inflammation producing cell types remains unanswered
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