1. Deoxycholic acid induces proinflammatory cytokine production by model oesophageal cells via lipid rafts.
- Author
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Quilty F, Freeley M, Gargan S, Gilmer J, and Long A
- Subjects
- Barrett Esophagus metabolism, Bile Acids and Salts chemistry, Caveolin 1 metabolism, Cell Line, Tumor, Cholesterol chemistry, Cholesterol metabolism, Cytokines metabolism, Gastroesophageal Reflux metabolism, Gene Expression drug effects, Humans, Inflammation, Interleukin-6 metabolism, Interleukin-8 metabolism, NF-kappa B metabolism, Neoplasms metabolism, Phosphorylation, Signal Transduction, beta-Cyclodextrins metabolism, src-Family Kinases metabolism, Deoxycholic Acid chemistry, Esophagus drug effects, Lipids chemistry, Membrane Microdomains chemistry
- Abstract
The bile acid component of gastric refluxate has been implicated in inflammation of the oesophagus including conditions such as gastro-oesophageal reflux disease (GORD) and Barrett's Oesophagus (BO). Here we demonstrate that the hydrophobic bile acid, deoxycholic acid (DCA), stimulated the production of IL-6 and IL-8 mRNA and protein in Het-1A, a model of normal oesophageal cells. DCA-induced production of IL-6 and IL-8 was attenuated by pharmacologic inhibition of the Protein Kinase C (PKC), MAP kinase, tyrosine kinase pathways, by the cholesterol sequestering agent, methyl-beta-cyclodextrin (MCD) and by the hydrophilic bile acid, ursodeoxycholic acid (UDCA). The cholesterol-interacting agent, nystatin, which binds cholesterol without removing it from the membrane, synergized with DCA to induce IL-6 and IL-8. This was inhibited by the tyrosine kinase inhibitor genistein. DCA stimulated the phosphorylation of lipid raft component Src tyrosine kinase (Src). while knockdown of caveolin-1 expression using siRNA resulted in a decreased level of IL-8 production in response to DCA. Taken together, these results demonstrate that DCA stimulates IL-6 and IL-8 production in oesophageal cells via lipid raft-associated signaling. Inhibition of this process using cyclodextrins represents a novel therapeutic approach to the treatment of inflammatory diseases of the oesophagus including GORD and BO., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
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