title: Involvement of nitric oxide with activation of Toll-like receptor 4 signaling in mice with dextran sodium sulfate-induced colitis.
abstract: Ulcerative colitis is an inflammatory bowel disease characterized by acute inflammation, ulceration, and bleeding of the colonic mucosa. Its cause remains unknown. Increases in adhesion molecules in vascular endothelium, and activated neutrophils releasing injurious molecules such as reactive oxygen species, are reportedly associated with the pathogenesis of dextran sodium sulfate (DSS)-induced colitis. Nitric oxide (NO) production derived from inducible NO synthase (iNOS) via activation of nuclear factor κB (NF-κB) has been reported. It is also reported that stimulation of Toll-like receptor 4 (TLR4) by lipopolysaccharide can activate NF-κB. In this study, we investigated the involvement of NO production in activation of the TLR4/NF-κB signaling pathway in mice with DSS-induced colitis. The addition of 5% DSS to the drinking water of male ICR mice resulted in increases in TLR4 protein in colon tissue and NF-κB p65 subunit in the nuclear fraction on day 3, increases in colonic tumor necrosis factor-α on day 4, and increases in P-selectin, intercellular adhesion molecule-1, NO2(-)/NO3(-), and nitrotyrosine in colonic mucosa on day 5. These activated inflammatory mediators and pathology of colitis were completely suppressed by treatment with a NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, as well as an iNOS inhibitor, aminoguanidine. Conversely, a NO-releasing compound, NOC-18, increased TLR4 levels and nuclear translocation of NF-κB p65 and exacerbated mucosal damage induced by DSS challenge. These data suggest that increases in TLR4 expression induced by drinking DSS-treated water might be directly or indirectly associated with NO overproduction.
authors.affiliation: Department of Biofunctional Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: Tun
authors.affiliation: Department of Biofunctional Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Yasukawa
authors.affiliation: Department of Biofunctional Science, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Japan Science and Technology Agency, PRESTO, Saitama 332-0012, Japan. Electronic address: yamada@pch.phar.kyushu-u.ac.jp.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000378:metabolism*; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D016166:Free Radical Scavengers; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D009603:Nitroso Compounds / Q000494:pharmacology; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D001565:Benzoates; D016166:Free Radical Scavengers; D006146:Guanidines; D007093:Imidazoles; D016328:NF-kappa B; C093285:NOC 18; D009603:Nitroso Compounds; D019007:P-Selectin; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; D009569:Nitric Oxide; D016264:Dextran Sulfate; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine
keywords: Colitis; Free radicals; Inflammation; NF-κB; Nitric oxide; TLR4