Abstract
A key morphological feature of inflammatory bowel disease (IBD) is the loss of the barrier function of intestinal epithelial cells. The present study investigates endoplasmic reticulum (ER) stress in addition to alterations in protein and membrane trafficking in a dextran sulfate sodium (DSS)-induced IBD-like phenotype of intestinal Caco-2 cells in culture. DSS treatment significantly reduced the transepithelial electric resistance (TEER) and increased the epithelial permeability of Caco-2 cells, without affecting their viability. This was associated with an alteration in the expression levels of inflammatory factors in addition to an increase in the expression of the ER stress protein markers, namely immunoglobulin-binding protein (BiP), C/EBP homologous protein (CHOP), activation transcription factor 4 (ATF4), and X-box binding protein (XBP1). The DSS-induced ER-stress resulted in impaired intracellular trafficking and polarized sorting of sucrase-isomaltase (SI) and dipeptidyl peptidase-4 (DPPIV), which are normally sorted to the apical membrane via association with lipid rafts. The observed impaired sorting was caused by reduced cholesterol levels and subsequent distortion of the lipid rafts. The data presented confirm perturbation of ER homeostasis in DSS-treated Caco-2 cells, accompanied by impairment of membrane and protein trafficking resulting in altered membrane integrity, cellular polarity, and hence disrupted barrier function.
Highlights
Intestinal homeostasis is maintained through the integrity of the mucosal barrier formed by epithelial cells and their secretions
We evaluated dextran sulfate sodium (DSS) treatment in inducing endoplasmic reticulum (ER) stress in Caco-2 cells
Five days post-confluent Caco-2 cells were treated with DSS, and the trans-epithelial electrical resistance (TEER) was evaluated over a period of 24 h
Summary
Intestinal homeostasis is maintained through the integrity of the mucosal barrier formed by epithelial cells and their secretions. Several studies have implicated decreased intestinal barrier function in inflammatory bowel disease (IBD) [1,2]. Biological membranes possess defined functional microdomains, or lipid rafts (LR), in which signaling proteins reside. These membranes are liquid-ordered lipid–protein assemblies enriched in cholesterol and sphingolipids that float within the liquid-disordered bilayer of cellular membranes [5]. Relatively little is known about the potential regulatory influence of LRs and non-lipid raft domains of the cell membrane on epithelial adhesion and barrier function under inflammatory conditions
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