Abstract
Inflammatory bowel disease (IBD) involves functional impairment of intestinal epithelial cells (IECs), concomitant with the infiltration of the lamina propria by inflammatory cells. We explored the reciprocal paracrine and direct interaction between human IECs and macrophages (MΦ) in a co-culture system that mimics some aspects of IBD. We investigated the expression of intercellular junctional proteins in cultured IECs under inflammatory conditions and in tissues from IBD patients. IECs establish functional gap junctions with IECs and MΦ, respectively. Connexin (Cx26) and Cx43 expression in cultured IECs is augmented under inflammatory conditions; while, Cx43-associated junctional complexes partners, E-cadherin, ZO-1, and β-catenin expression is decreased. The expression of Cx26 and Cx43 in IBD tissues is redistributed to the basal membrane of IEC, which is associated with decrease in junctional complex proteins’ expression, collagen type IV expression and infiltration of MΦ. These data support the notion that the combination of paracrine and hetero-cellular communication between IECs and MΦs may regulate epithelial cell function through the establishment of junctional complexes between inflammatory cells and IECs, which ultimately contribute to the dys-regulation of intestinal epithelial barrier.
Highlights
Known, about the role of GJIC in the inflammation process and vice versa some reports have suggested that some pro-inflammatory mediators are involved in its regulation[21,22,23]
We have shown that cytokines such as IL-1, whose levels are increased in the mucosa of inflammatory bowel diseases (IBD) patients, mediate their effects on intestinal epithelial cells (IECs) through two distinct lipid metabolic pathways, both of which lead to increased expression of cyclooxygenase-2 enzyme and increased production of Prostaglandin E2 (PGE2)[26,27]
Immune cells infiltrate the submucosa, juxtaposed to the epithelial lining of the intestine. This close proximity of immune cells to the epithelial cells suggests that a cross talk between these two cell types exists either directly through gap junctional channels or through soluble mediators and exosomes
Summary
Known, about the role of GJIC in the inflammation process and vice versa some reports have suggested that some pro-inflammatory mediators are involved in its regulation[21,22,23]. We have shown that cytokines such as IL-1, whose levels are increased in the mucosa of IBD patients, mediate their effects on IECs through two distinct lipid metabolic pathways, both of which lead to increased expression of cyclooxygenase-2 enzyme and increased production of Prostaglandin E2 (PGE2)[26,27]. The overall aim of this study is to explore the nature of the interaction between human IECs and MΦ, to identify the connexin proteins present in human IECs, and to assess their regulation under inflammatory conditions and their potential role in the etiology and pathophysiology of IBD
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