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T oll‐like receptor ( TLR ) 2 agonists ameliorate indomethacin‐induced murine ileitis by suppressing the TLR 4 signaling
Author(s) -
Narimatsu Kazuyuki,
Higashiyama Masaaki,
Kurihara Chie,
Takajo Takeshi,
Maruta Koji,
Yasutake Yuichi,
Sato Hirokazu,
Okada Yoshikiyo,
Watanabe Chikako,
Komoto Shunsuke,
Tomita Kengo,
Nagao Shigeaki,
Miura Soichiro,
Hokari Ryota
Publication year - 2015
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.12980
Subject(s) - ileitis , medicine , lipopolysaccharide , pharmacology , receptor , tumor necrosis factor alpha , immunology , intravital microscopy , colitis , microcirculation , disease , crohn's disease
Background and Aim Few drugs have been found satisfactory in the treatment of nonsteroidal anti‐inflammatory drugs ( NSAIDs )‐induced enteropathy. T oll‐like receptor ( TLR ) 4 and aberrant leukocyte migration to the intestinal mucosa are reported to be involved in the pathology of intestinal enteropathy and TLR 2 agonists have been found to evoke hyposensitivity to TLR 4 stimulation in vitro. In this study, we investigated whether and how lipoarabinomannan ( LAM ) or lipoteichoic acid ( LTA ), TLR 2 agonists, attenuated indomethacin ( IND )‐induced intestinal damage. Methods LAM (0.5 mg/kg) or LTA (15 mg/kg) was administered intraperitoneally to mice before IND (10 mg/kg) administration. Disease activity was evaluated macroscopically and histologically. In the migration analysis, fluorescence‐labeled leukocyte movement in the intestinal microvessels was observed by intravital microscopy. Expression of P ‐selectin, MAdCAM ‐1, TLR 2, TLR 4, and F 4/80 was observed immunohistochemically. In the in vitro analysis, RAW 264.7 macrophage cells were preincubated with LAM and stimulated with lipopolysaccharide ( LPS ), and the mRNA expression levels of TLR 4, tumor necrosis factor‐α, and interleukin‐12p40 were measured. Results Pretreatment with LAM or LTA significantly decreased IND ‐induced injury as well as decreased leukocyte infiltration. Pretreatment with LAM decreased IND ‐induced TLR 4 expression on F 4/80 + macrophages, the level of P ‐selectin expression, and leukocyte migration in the small intestinal vessels. In the in vitro study, a single administration of LAM decreased TLR 4 mRNA expression and inhibited the increase in mRNA expression of inflammatory cytokines by LPS in a dose‐dependent manner. Conclusion TLR 2 agonists attenuated IND ‐induced small intestinal lesions and leukocyte infiltration probably by suppressing the TLR 4 signaling pathway in tissue macrophages.