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Suppression of Toll-like receptor 4 activation by caffeic acid phenethyl ester is mediated by interferenceof LPS binding to MD2

Title
Suppression of Toll-like receptor 4 activation by caffeic acid phenethyl ester is mediated by interferenceof LPS binding to MD2
Authors
Kim S.Y.Koo J.E.Seo Y.J.Tyagi N.Jeong E.Choi J.Lim K.-M.Park Z.-Y.Lee J.Y.
Ewha Authors
임경민
SCOPUS Author ID
임경민scopus
Issue Date
2013
Journal Title
British Journal of Pharmacology
ISSN
0007-1188JCR Link
Citation
vol. 168, no. 8, pp. 1933 - 1945
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Background and Purpose Toll-like receptors (TLRs) play a crucial role in recognizing invading pathogens and endogenous danger signal to induce immune and inflammatory responses. Since dysregulation of TLRs enhances the risk of immune disorders and chronic inflammatory diseases, modulation of TLR activity by phytochemicals could be useful therapeutically. We investigated the effect of caffeic acid phenethyl ester (CAPE) on TLR-mediated inflammation and the underlying regulatory mechanism. Experimental Approach Inhibitory effects of CAPE on TLR4 activation were assessed with in vivo murine skin inflammation model and in vitro production of inflammatory mediators in macrophages. In vitro binding assay, cell-based immunoprecipitation study and liquid chromatography-tandem mass spectrometry analysis were performed to determine lipopolysaccharide (LPS) binding to MD2 and to identify the direct binding site of CAPE in MD2. Key Results Topical application of CAPE attenuated dermal inflammation and oedema induced by intradermal injection of LPS (a TLR4 agonist). CAPE suppressed production of inflammatory mediators and activation of NFκB and interferon-regulatory factor 3 (IRF3) in macrophages stimulated with LPS. CAPE interrupted LPS binding to MD2 through formation of adduct specifically with Cys133 located in hydrophobic pocket of MD2. The inhibitory effect on LPS-induced IRF3 activation by CAPE was not observed when 293T cells were reconstituted with MD2 (C133S) mutant. Conclusions and Implications Our results show a novel mechanism for anti-inflammatory activity of CAPE to prevent TLR4 activation by interfering with interaction between ligand (LPS) and receptor complex (TLR4/MD2). These further provide beneficial information for the development of therapeutic strategies to prevent chronic inflammatory diseases. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
DOI
10.1111/bph.12091
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약학대학 > 약학과 > Journal papers
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