A complex of soluble MD-2 and lipopolysaccharide serves as an activating ligand for Toll-like receptor 4
| Autor: | Cynthia A. Leifer, Alessandra Mazzoni, Margaret N. Kennedy, David M. Segal, ChangWoo Lee, Kottarappat N. Dileepan, Gregory E. D. Mullen |
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| Rok vydání: | 2004 |
| Předmět: |
Lymphocyte antigen 96
Lipopolysaccharides Time Factors CD14 Genetic Vectors Lipopolysaccharide Receptors Lymphocyte Antigen 96 Enzyme-Linked Immunosorbent Assay Receptors Cell Surface Plasma protein binding Biology Endoplasmic Reticulum Ligands Biochemistry Models Biological Cell Line Lipid A Humans Molecular Biology chemistry.chemical_classification Inflammation Toll-like receptor Membrane Glycoproteins Interleukin-6 Endoplasmic reticulum Cell Membrane Interleukin-8 Toll-Like Receptors NF-kappa B Temperature Cell Biology Precipitin Tests Cell biology Protein Structure Tertiary Toll-Like Receptor 4 chemistry Antigens Surface TLR4 lipids (amino acids peptides and proteins) Glycoprotein Protein Binding |
| Zdroj: | The Journal of biological chemistry. 279(33) |
| ISSN: | 0021-9258 |
| Popis: | MD-2, a glycoprotein that is essential for the innate response to lipopolysaccharide (LPS), binds to both LPS and the extracellular domain of Toll-like receptor 4 (TLR4). Following synthesis, MD-2 is either secreted directly into the medium as a soluble, active protein, or binds directly to TLR4 in the endoplasmic reticulum before migrating to the cell surface. Here we investigate the function of the secreted form of MD-2. We show that secreted MD-2 irreversibly loses activity over a 24-h period at physiological temperature. LPS, but not lipid A, prevents this loss in activity by forming a stable complex with MD-2, in a CD14-dependent process. Once formed, the stable MD-2.LPS complex activates TLR4 in the absence of CD14 or free LPS indicating that the activating ligand of TLR4 is the MD-2.LPS complex. Finally we show that the MD-2.LPS complex, but not LPS alone, induces epithelial cells, which express TLR4 but not MD-2, to secrete interleukin-6 and interleukin-8. We propose that the soluble MD-2.LPS complex plays a crucial role in the LPS response by activating epithelial and other TLR4(+)/MD-2(-) cells in the inflammatory microenvironment. |
| Databáze: | OpenAIRE |
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