Sulforaphane Suppresses Oligomerization of TLR4 in a Thiol-Dependent Manner

Title
Sulforaphane Suppresses Oligomerization of TLR4 in a Thiol-Dependent Manner
Author(s)
곽미경Hyung Sun Youn[Hyung Sun Youn]Yoon Sun Kim[Yoon Sun Kim]Zee Yong Park[Zee Yong Park]So Young Kim[So Young Kim]Na Young Choi[Na Young Choi]Sun Myung Joung[Sun Myung Joung]Jung A. Seo[Jung A. Seo]Kyung-Min Lim[Kyung-Min Lim]Daniel H. Hwang[Daniel H. Hwang]Joo Young Lee[Joo Young Lee]
Keywords
NF-KAPPA-B; TOLL-LIKE RECEPTOR-3; DOUBLE-STRANDED-RNA; SIGNALING PATHWAY; TLR4-MD-2 COMPLEX; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; GENE-EXPRESSION; ACTIVATION; DISTINCT
Issue Date
201001
Publisher
AMER ASSOC IMMUNOLOGISTS
Citation
JOURNAL OF IMMUNOLOGY, v.184, no.1, pp.411 - 419
Abstract
TLRs are pattern recognition receptors that detect invading microorganisms and nonmicrobial endogenous molecules to trigger immune and inflammatory responses during host defense and tissue repair. TLR activity is closely linked to the risk of many inflammatory diseases and immune disorders. Therefore, TLR signaling pathways can provide efficient therapeutic targets for chronic diseases. Sulfuraphane (SFN), an isothiocyanate, has been well known for its anti-inflammatory activities. In this study, we investigated the modulation of TLR activity by SFN and the underlying mechanism. SFN suppressed ligand-induced and ligand-independent TLR4 activation because it prevented IL-1R-associated kinase-1 degradation, activation of NF-kappa B and IFN regulatory factor 3, and cyclooxygenase-2 expression induced by LPS or overexpression of TLR4. Receptor oligomerization, which is one of the initial and critical events of TLR4 activation, was suppressed by SFN, resulting in the downregulation of NF-kappa B activation. SFN formed adducts with cysteine residues in the extracellular domain of TLR4 as confirmed by liquid chromatography-tandem mass spectrometry analysis and the inhibitory effects of SFN on oligomerization and NF-kappa B activation were reversed by thiol donors (DTT and N-acetyl-L-cysteine). These suggest that the reactivity of SFN to sulfhydryl moiety contributes to its inhibitory activities. Blockade of TLR4 signaling by SFN resulted in the reduced production of inflammatory cytokines and the decreased dermal inflammation and edema in vivo in experimental inflammatory. animal models. Collectively, our results demonstrated that SFN downregulated TLR4 signaling through the suppression of oligomerization process in a thiol-dependent manner. These present a novel mechanism for beneficial effects of SFN and a novel anti-inflammatory target in TLR4 signaling. The Journal of Immunology, 2010, 184: 411-419.
URI
http://hdl.handle.net/YU.REPOSITORY/23024http://dx.doi.org/10.4049/jimmunol.0803988
ISSN
0022-1767
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약학대학 > 약학부 > Articles
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