Role of ROCK/NF-κB/AQP8 signaling in ethanol-induced intestinal epithelial barrier dysfunction

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

The present study aimed to investigate the signaling pathways and the underlying molecular mechanisms involved in ethanol-induced intestinal epithelial barrier (IEB) dysfunction. Therefore, an in vitro experimental model of IEB was established using an ethanol-treated Caco-2 intestinal epithelial cell monolayer. The results confirmed that Rho-associated kinases (ROCKs), namely ROCK1 and ROCK2, were involved in the underlying pathway of ethanol-induced IEB dysfunction. Ethanol exposure significantly increased the expression of both ROCK isoforms and the activity of nuclear factor κB (NF-κB). Furthermore, ROCK1- and ROCK2-specific small interfering RNAs (siRNAs), and the NF-κB inhibitor ammonium pyrrolidine dithiocarbamate partially inhibited transepithelial electrical resistance in Caco-2 cells in an in vitro IEB model. In addition, ROCK1- and ROCK2-specific siRNAs inhibited the activity of NF-κB, thereby downregulating the expression of aquaporin 8 (AQP8). Taken together, the results of the present study suggested that ROCK1/ROCK2-mediated activation of NF-κB and upregulation of AQP8 expression levels may represent a novel mechanism of ethanol-induced impairment of IEB function.

Related collections

Most cited references 28

Record: found
Abstract: found
Article: not found

Rho kinase (ROCK) inhibitors.

M Seto, Kensuke Noma, K K Liao (2007)

The Rho kinase (ROCK) isoforms, ROCK1 and ROCK2, were initially discovered as downstream targets of the small GTP-binding protein Rho. Because ROCKs mediate various important cellular functions such as cell shape, motility, secretion, proliferation, and gene expression, it is likely that this pathway will intersect with other signaling pathways known to contribute to cardiovascular disease. Indeed, ROCKs have already been implicated in the regulation of vascular tone, proliferation, inflammation, and oxidative stress. However, it is not entirely clear how ROCKs are regulated, what some of their downstream targets are, and whether ROCK1 and ROCK2 mediate different cellular functions. Clinically, inhibition of ROCK pathway is believed to contribute to some of the cardiovascular benefits of statin therapy that are independent of lipid lowering (ie, pleiotropic effects). To what extent ROCK activity is inhibited in patients on statin therapy is not known, but it may have important clinical implications. Indeed, several pharmaceutical companies are already actively engaged in the development of ROCK inhibitors as the next generation of therapeutic agents for cardiovascular disease because evidence from animal studies suggests the potential involvement of ROCK in hypertension and atherosclerosis.

0 comments Cited 97 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation.

Prashant K Nighot, Chien-An Andy Hu, Thomas Y. Ma (2015)

Autophagy is an intracellular degradation pathway and is considered to be an essential cell survival mechanism. Defects in autophagy are implicated in many pathological processes, including inflammatory bowel disease. Among the innate defense mechanisms of intestinal mucosa, a defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in the causation and progression of inflammatory bowel disease by allowing increased antigenic permeation. The cross-talk between autophagy and the TJ barrier has not yet been described. In this study, we present the novel finding that autophagy enhances TJ barrier function in Caco-2 intestinal epithelial cells. Nutrient starvation-induced autophagy significantly increased transepithelial electrical resistance and reduced the ratio of sodium/chloride paracellular permeability. Nutrient starvation reduced the paracellular permeability of small-sized urea but not larger molecules. The role of autophagy in the modulation of paracellular permeability was confirmed by pharmacological induction as well as pharmacological and genetic inhibition of autophagy. Consistent with the autophagy-induced reduction in paracellular permeability, a marked decrease in the level of the cation-selective, pore-forming TJ protein claudin-2 was observed after cell starvation. Starvation reduced the membrane presence of claudin-2 and increased its cytoplasmic, lysosomal localization. Therefore, our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of the TJ protein claudin-2.

0 comments Cited 80 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Effects of Ethanol and Acetaldehyde on Tight Junction Integrity: In Vitro Study in a Three Dimensional Intestinal Epithelial Cell Culture Model

Elhaseen Elamin, Daisy Jonkers, Kati Juuti-Uusitalo … (2012)

Background Intestinal barrier dysfunction and translocation of endotoxins are involved in the pathogenesis of alcoholic liver disease. Exposure to ethanol and its metabolite, acetaldehyde at relatively high concentrations have been shown to disrupt intestinal epithelial tight junctions in the conventional two dimensional cell culture models. The present study investigated quantitatively and qualitatively the effects of ethanol at concentrations detected in the blood after moderate ethanol consumption, of its metabolite acetaldehyde and of the combination of both compounds on intestinal barrier function in a three-dimensional cell culture model. Methods and Findings Caco-2 cells were grown in a basement membrane matrix (Matrigel™) to induce spheroid formation and were then exposed to the compounds at the basolateral side. Morphological differentiation of the spheroids was assessed by immunocytochemistry and transmission electron microscopy. The barrier function was assessed by the flux of FITC-labeled dextran from the basal side into the spheroids' luminal compartment using confocal microscopy. Caco-2 cells grown on Matrigel assembled into fully differentiated and polarized spheroids with a central lumen, closely resembling enterocytes in vivo and provide an excellent model to study epithelial barrier functionality. Exposure to ethanol (10–40 mM) or acetaldehyde (25–200 µM) for 3 h, dose-dependently and additively increased the paracellular permeability and induced redistribution of ZO-1 and occludin without affecting cell viability or tight junction-encoding gene expression. Furthermore, ethanol and acetaldehyde induced lysine residue and microtubules hyperacetylation. Conclusions These results indicate that ethanol at concentrations found in the blood after moderate drinking and acetaldehyde, alone and in combination, can increase the intestinal epithelial permeability. The data also point to the involvement of protein hyperacetylation in ethanol- and acetaldehyde-induced loss of tight junctions integrity.

0 comments Cited 46 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Mol Med Rep

Journal ID (iso-abbrev): Mol Med Rep

Title: Molecular Medicine Reports

Publisher: D.A. Spandidos

ISSN (Print): 1791-2997

ISSN (Electronic): 1791-3004

Publication date (Print): September 2020

Publication date (Electronic): 09 July 2020

Publication date PMC-release: 09 July 2020

Volume: 22

Issue: 3

Pages: 2253-2262

Affiliations

[1 ]Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China

[2 ]Department of Ophthalmology, The 4th People's Hospital of Shenyang, Shenyang, Liaoning 110031, P.R. China

Author notes

Correspondence to: Dr Jing Tong, Department of Gastroenterology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Shenyang, Liaoning 110001, P.R. China, E-mail: realll30@ 123456126.com

Article

Publisher ID: mmr-22-03-2253

DOI: 10.3892/mmr.2020.11318

PMC ID: 7411333

PubMed ID: 32705263

SO-VID: 9d9ac287-a5e4-4416-89e8-fbed6e49a791

License:

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Role of ROCK/NF-κB/AQP8 signaling in ethanol-induced intestinal epithelial barrier dysfunction

Read this article at

Abstract

Related collections

Neuronal Signaling

Most cited references 28

Rho kinase (ROCK) inhibitors.

Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation.

Effects of Ethanol and Acetaldehyde on Tight Junction Integrity: In Vitro Study in a Three Dimensional Intestinal Epithelial Cell Culture Model

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 269

Cited by 2

Most referenced authors 578