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The Effects of Alcohol on MAP‐Kinase Tight Junction Regulation in Lymphatic Endothelial Cells
Author(s) -
Herrera Matthew J.,
Souza-Smith Flavia
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04974
Subject(s) - adherens junction , tight junction , microbiology and biotechnology , occludin , lymphatic endothelium , endothelial stem cell , protein kinase a , kinase , cell junction , chemistry , biology , lymphatic system , cell , biochemistry , immunology , in vitro , cadherin
Alcohol is known to cause lymphatic vessel hyperpermeability, leading to disrupted immune crosstalk between the gut and mesenteric lymph nodes. However, the mechanism of this alcohol‐induced hyperpermeability is unknown. The permeability of endothelial cell layers is correlated to decreased expression of certain proteins located at cell‐to‐cell contacts, known as tight junction (TJ) and adherens junctions (AJ). Proteins in these junctions, which predominantly include Claudin, Occludin, ZO‐1, and VE‐Cadherin, are shown to be regulated by MAP‐kinase proteins Erk1/2 and p38. In various endothelial cell types, alcohol increases phosphorylation of MAP‐Kinase proteins, leading to alterations in expression of TJ proteins. We hypothesize that alcohol induces lymphatic endothelial cell permeability via disruption of lymphatic endothelial cell TJs through activation of the MAP‐kinase pathway. To characterize the effects of alcohol on cellular permeability, we used and in vitro model of rat lymphatic endothelial cells. Alcohol‐supplemented medium was added at concentrations of 25 mM and 50 mM to confluent cells, and the transendothelial resistance across the cell monolayer, which is inversely related to permeability, was measured. After characterization of permeability, we measured phosphorylated states of MAP‐kinase proteins, specifically Erk1/2 and p38, at the time point that was associated with the maximum change in resistance. Our results show that alcohol increases the permeability of the endothelial cell monolayer compared to controls lacking alcohol. We also found that, at 50 mM alcohol, there was an increase in phosphorylated levels of p38 compared to controls. We predict that p38 might be affecting the expression or translocation of TJ and AJ proteins involved in forming and maintaining cell‐to‐cell adhesion, leading to increased permeability and lymphatic vessel leakage. Support or Funding Information LSUHSC Department of Physiology NIAAA ‐ K01 AA026640‐01 (FSS)