Dysregulation of junctional adhesion molecule‐A contributes to ethanol‐induced barrier disruption in intestinal epithelial cell monolayers
Year: 2017
Type: article
Abstract: Alcohol consumption promotes loss of intestinal barrier function. However, mechanisms by which ethanol affects the tight junction (TJ), the cellular structure responsible for maintaining the gut epithelial barrier, are not well understood. Three classes of transmembrane proteins comprise TJs: occludin, claudins, and junctional adhesion molecules (JAMs). It has recently been postulated that JAM-A (F11R), the most abundant JAM expressed in intestinal epithelium, regulates "leak" pathway flux, a paracellular route for the nonselective permeation of large solutes. Since transluminal flux of many gut-derived antigens occurs through this pathway, we investigated the role of JAM-A in ethanol-induced disruption of the intestinal epithelial barrier. Using Caco-2 and SK-CO15 monolayers, we found that ethanol induced a dose- and time-dependent decrease in JAM-A protein expression to about 70% of baseline levels. Alcohol also reduced Ras-related protein 2 (Rap2) activity, and enhanced myosin light chain kinase (MLCK) activity, changes consistent with impaired JAM-A signaling. Stable overexpression and shRNA-mediated knockdown of JAM-A were employed to investigate the role of JAM-A in paracellular-mediated flux following alcohol exposure. The paracellular flux of 40-kDa fluorescein isothiocynate (FITC)-dextran following ethanol treatment was decreased by the overexpression of JAM-A; conversely, flux was enhanced by JAM-A knockdown. Thus, we conclude that ethanol-mediated control of JAM-A expression and function contributes to mechanisms by which this chemical induces intestinal epithelial leakiness.
Source: Physiological Reports
DOI: 10.14814/phy2.13541
Authors: Daniel M. Chopyk, Pradeep Kumar, Reben Raeman, Yunshan Liu, Tekla Smith, Frank A. Anania
Institution: Emory University
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,050
Awards: Medical Scientist Training Program, G2266079415, G3202922939, Multiple Mechanisms of the Matricellular Protein Periostin in the Pathogenesis of Hepatic Fibrosis, Defects in junctional adhesion molecule-A and Intestinal Permeability: Identification of Novel Mechanisms Driving Non-Alcoholic Steatohepatitis, Multiple Molecular Mechanisms for Adiponectin Therapy in Hepatic Fibrogenesis, A pivotal role for junctional adhesion molecule-A in alcoholic liver injury, G9000030289, Role of CD4 T cells in the pathogenesis of non-alcoholic steatohepatitis, Southern California Research Center for ALPD and Cirrhosis, G964971120
OpenAlex ID: W2772535512