Increased release of sMD-2 during human endotoxemia and sepsis: a role for endothelial cells.

T.G. Wolfs, I. Dunn-Siegrist, C. van 't Veer, C.M. Hodin, W.T.V. Germeraad, M. van Zoelen, R.J. van Suylen, C.J. Peutz-Kootstra, G. Elson, J. Pugin, W.A. Buurman

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

MD-2 is the crucial cofactor of TLR4 in the detection of LPS. Here, we show that soluble MD-2 (sMD-2) circulates in plasma of healthy individuals as a polymeric protein. The total amount of sMD-2 in septic plasma was strongly elevated and contained both sMD-2 polymers and monomers, the latter representing the putative biologically active form of MD-2. Moreover, during experimental human endotoxemia, the monomeric and total sMD-2 content in plasma increased with the kinetics of an acute phase protein. The increase in sMD-2 monomers was paralleled by enhanced TLR4 costimulatory activity. The presence of functional sMD-2 during endotoxemia and sepsis was confirmed by immunodepletion. Immunohistochemistry revealed that MD-2 expression in septic patients was strongly enhanced on endothelium and multiple inflammatory cells in lung and liver. In vitro studies showed that sMD-2 release appears to be restricted to endothelial cells and dendritic cells. Release of sMD-2 by endothelial cells was strongly enhanced by LPS and TNF-alpha stimulation. Taken together, this study demonstrates the increase of both circulating polymeric and functional monomeric sMD-2 during endotoxemia and sepsis, and evidence is provided that the endothelium is involved in this process. AU - LA - ENG PT - JOURNAL ARTICLE DEP - 20080331 TA - Mol Immunol JT - JID - 7905289
Original languageEnglish
Pages (from-to)3268-3277
JournalMolecular Immunology
Volume45
Issue number11
DOIs
Publication statusPublished - 1 Jan 2008

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