期刊
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
卷 30, 期 11, 页码 1610-1617出版社
WILEY-BLACKWELL
DOI: 10.1111/jgh.12980
关键词
lipoarabinomannan; lipoteichoic acid; nonsteroidal anti-inflammatory agents; Toll-like receptors
资金
- National Defense Medical College
- Smoking Research Foundation
- Intractable Disease, the Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare
Background and AimFew drugs have been found satisfactory in the treatment of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy. Toll-like receptor (TLR) 4 and aberrant leukocyte migration to the intestinal mucosa are reported to be involved in the pathology of intestinal enteropathy and TLR2 agonists have been found to evoke hyposensitivity to TLR4 stimulation in vitro. In this study, we investigated whether and how lipoarabinomannan (LAM) or lipoteichoic acid (LTA), TLR2 agonists, attenuated indomethacin (IND)-induced intestinal damage. MethodsLAM (0.5mg/kg) or LTA (15mg/kg) was administered intraperitoneally to mice before IND (10mg/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, TLR2, TLR4, and F4/80 was observed immunohistochemically. In the in vitro analysis, RAW264.7 macrophage cells were preincubated with LAM and stimulated with lipopolysaccharide (LPS), and the mRNA expression levels of TLR4, tumor necrosis factor-, and interleukin-12p40 were measured. ResultsPretreatment with LAM or LTA significantly decreased IND-induced injury as well as decreased leukocyte infiltration. Pretreatment with LAM decreased IND-induced TLR4 expression on F4/80(+) 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 TLR4 mRNA expression and inhibited the increase in mRNA expression of inflammatory cytokines by LPS in a dose-dependent manner. ConclusionTLR2 agonists attenuated IND-induced small intestinal lesions and leukocyte infiltration probably by suppressing the TLR4 signaling pathway in tissue macrophages.
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