Abstract
Lipopolysaccharide (LPS)-mediated activation of toll-like receptor-4 (TLR-4) complex induces specific signaling pathways, such as the myeloid differentiation primary response protein-88 (MyD88) and the tumor necrosis factor receptor-associated factor-6 (TRAF-6), involving NF-kappaB activation. As previous data reported that hyaluronan (HA) and heparan sulfate (HS) may interact with TLR-4, the aim of this study was to investigate whether glycosaminoglycans (GAGs) may modulate the TLR-4 receptor in a model of LPS-induced inflammatory cytokines in mouse chondrocytes. LPS stimulation up-regulated all inflammation parameters. The GAG treatment produced various effects: HA reduced MyD88 and TRAF-6 levels and NF-kappaB activation at the higher dose only, and exerted a very low anti-inflammatory effect; chondroitin-4-sulfate (C4S) and chondroitin-6-sulfate significantly inhibited MyD88, TRAF-6 and NF-kappaB activation, the inflammation cytokines, and inducible nitric oxide synthase; HS, like C4S, significantly reduced MyD88, TRAF-6, NF-kappaB and inflammation. Specific TLR-4 blocking antibody confirmed that TLR-4 was the target of GAG action.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibody Specificity
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Blotting, Western
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Cattle
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Cells, Cultured
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Chondrocytes / drug effects*
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Chondrocytes / metabolism*
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Gene Expression Regulation / drug effects
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Glycosaminoglycans / pharmacology*
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Inflammation / metabolism
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Lipopolysaccharides / pharmacology*
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Matrix Metalloproteinase 13 / genetics
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Matrix Metalloproteinase 13 / metabolism
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Mice
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism
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NF-kappa B / metabolism
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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TNF Receptor-Associated Factor 6 / genetics
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TNF Receptor-Associated Factor 6 / metabolism
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / immunology
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Toll-Like Receptor 4 / metabolism*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Glycosaminoglycans
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Interleukin-1beta
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Lipopolysaccharides
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Myeloid Differentiation Factor 88
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NF-kappa B
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RNA, Messenger
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TNF Receptor-Associated Factor 6
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Toll-Like Receptor 4
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Tumor Necrosis Factor-alpha
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Nitric Oxide Synthase Type II
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Matrix Metalloproteinase 13