A complex of soluble MD-2 and lipopolysaccharide serves as an activating ligand for Toll-like receptor 4

M N Kennedy, G E D Mullen, C A Leifer, C Lee, A Mazzoni, K N Dileepan, D M Segal

Research output: Contribution to journalArticlepeer-review

104 Citations (Scopus)

Abstract

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
Original languageEnglish
Pages (from-to)34698 - 34704
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number33
DOIs
Publication statusPublished - 13 Aug 2004

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