Serotonin regulates innate immune responses of colon epithelial cells through Nox2-derived reactive oxygen species

Title
Serotonin regulates innate immune responses of colon epithelial cells through Nox2-derived reactive oxygen species
Author(s)
김정애수실렉미박수영구세광[구세광]
Keywords
INFLAMMATORY-BOWEL-DISEASE; NF-KAPPA-B; MONOCYTE-CHEMOATTRACTANT PROTEIN-1; ULCERATIVE-COLITIS; NADPH OXIDASES; OXIDATIVE STRESS; GENE-EXPRESSION; RAT COLITIS; PHOSPHORYLATION; ACTIVATION
Issue Date
201404
Publisher
ELSEVIER SCIENCE INC
Citation
FREE RADICAL BIOLOGY AND MEDICINE, v.69, pp.377 - 389
Abstract
Changes in serotonin (5-hydroxytryptamine, 5-HT) content in the gut of patients with inflammatory bowel disease (IBD) and animal models of colitis suggest an important role of 5-HT in the pathogenesis of IBD. In this study, we examined the role and mechanism of action of 5-HT in the inflammatory response of colon epithelial cells in vitro and in vivo. In colon epithelial cells (CCD 841, HT-29, Caco-2), direct application of 5-HT induced production of reactive oxygen species (ROS) and monocyte-epithelial adhesion, an initial event of inflammation, which were blocked not only by 5-HT receptor antagonists (tropisetron, RS39604, and SB269970), antioxidants (ascorbic acid, apocynin), and various inhibitors of NADPH oxidase (DPI), CREB (KG-501), and NF-B-k (PDTC), but also by transfection with Nox2 siRNA. Nox2-derived production of ROS corresponded with the rapid and brief activation of Rac. In addition, 5-HT induced Nox2, p67(phox), and Duox2 without altering the level of Noxl or Duox1 in colon epithelial cells, and silencing of Nox2 suppressed 5-HT-induced Duox2 increase. 5-HT also induced an increase in the expression of MCP-1, IL-8, and ICAM-1 and a decrease in E-cadherin expression. Exogenous application of 5-HT to rat colon through the rectum caused a minimal level of inflammation, which was demonstrated by histological examination, MPO activity, and inflammatory cytokine induction. However, 5-HT combined with a low dose of 2,4,6-trinitrobenzene sulfonic acid (TNBS), the level of which caused a minimal level of colitis, exaggerated colon inflammation accompanied by much more enhanced induction of inflammatory cytokines, IL-6, IL-8, and MCP-1, indicating that colon epithelial cells directly exposed to 5-HT are primed toward inflammation. In the colon at the lesion site, treatment with 5-HT resulted in an increase in the level of epithelial Nox2 but not of constitutively expressed Noxl, which is the opposite result of TNBS treatment. Furthermore, 5-HT treatment of Nox2-knockout mice did not induce colon inflammation, in contrast to 5-HT-treated wild-type mice. The results demonstrate that colon epithelial cells directly exposed to 5-HT are primed for inflammatory reactions, which is an important innate immune response, and the underlying mechanism for the priming is associated with Nox2-activated signaling pathways, including ERK/p38 MAPK, NF-B-k, and CREB. (c) 2014 Elsevier Inc. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/32531http://dx.doi.org/10.1016/j.freeradbiomed.2014.02.003
ISSN
0891-5849
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약학대학 > 약학부 > Articles
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