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SHR Neuro Krebs Kardio Lipid

Schaefer, L; Babelova, A; Kiss, E; Hausser, HJ; Baliova, M; Krzyzankova, M; Marsche, G; Young, MF; Mihalik, D; Götte, M; Malle, E; Schaefer, RM; Gröne, HJ.
The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages.
J Clin Invest. 2005; 115(8): 2223-2233. [OPEN ACCESS]
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Autor/innen der Med Uni Graz:
Malle Ernst
Marsche Gunther
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Number of Figures: 7
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Abstract:
Biglycan, a small leucine-rich proteoglycan, is a ubiquitous ECM component; however, its biological role has not been elucidated in detail. Here we show that biglycan acts in macrophages as an endogenous ligand of TLR4 and TLR2, which mediate innate immunity, leading to rapid activation of p38, ERK, and NF-kappaB and thereby stimulating the expression of TNF-alpha and macrophage inflammatory protein-2 (MIP-2). In agreement, the stimulatory effects of biglycan are significantly reduced in TLR4-mutant (TLR4-M), TLR2-/-, and myeloid differentiation factor 88-/- (MyD88-/-) macrophages and completely abolished in TLR2-/-/TLR4-M macrophages. Biglycan-null mice have a considerable survival benefit in LPS- or zymosan-induced sepsis due to lower levels of circulating TNF-alpha and reduced infiltration of mononuclear cells in the lung, which cause less end-organ damage. Importantly, when stimulated by LPS-induced proinflammatory factors, macrophages themselves are able to synthesize biglycan. Thus, biglycan, upon release from the ECM or from macrophages, can boost inflammation by signaling through TLR4 and TLR2, thereby enhancing the synthesis of TNF-alpha and MIP-2. Our results provide evidence for what is, to our knowledge, a novel role of the matrix component biglycan as a signaling molecule and a crucial proinflammatory factor. These findings are potentially relevant for the development of new strategies in the treatment of sepsis.
Find related publications in this database (using NLM MeSH Indexing)
Adaptor Proteins, Signal Transducing -
Animals -
Antigens, Differentiation - genetics
Extracellular Matrix - genetics
Extracellular Matrix Proteins - genetics
Inflammation - genetics
Lipopolysaccharides - toxicity
Lung - metabolism
Macrophages, Alveolar - metabolism
Membrane Glycoproteins - genetics
Mice - genetics
Mice, Knockout - genetics
Myeloid Differentiation Factor 88 - genetics
NF-kappa B - metabolism
Proteoglycans - genetics
Receptors, Cell Surface - genetics
Receptors, Immunologic - genetics
Sepsis - chemically induced
Signal Transduction - drug effects
Toll-Like Receptor 2 - drug effects
Toll-Like Receptor 4 - drug effects
Toll-Like Receptors - drug effects
Tumor Necrosis Factor-alpha - biosynthesis
Zymosan - toxicity
p38 Mitogen-Activated Protein Kinases - metabolism

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