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J. Biol. Chem., Vol. 279, Issue 33, 34698-34704, August 13, 2004
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From the
Experimental Immunology Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892, the Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland, 20892, and the ¶Department of Medicine, The University of Kansas Medical Center, Kansas City, Kansas 66160
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.
Received for publication, May 17, 2004
* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| To whom correspondence should be addressed: Bldg. 10, Rm. 4B36, National Institutes of Health, Bethesda, MD 20892-1360. Tel.: 301-496-3109; Fax: 301-496-0887; E-mail: dave_segal{at}nih.gov.
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