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

Wolfs, Tim G.A.M.
van't Veer, Cornelis
Hodin, Caroline M.I.M.
Germeraad, Wilfred T.V.
van Zoelen, Marieke A.D.
van Suylen, Robert-Jan
Peutz-Kootstra, Carine J.
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Published in Molecular Immunology. 2008, vol. 45, no. 11, p. 3268-77
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.
Keywords AdultCase-Control StudiesEndothelial Cells/drug effects/immunology/metabolism/pathologyEndotoxemia/immunology/metabolismFemaleHematopoietic System/cytology/drug effectsHumansKineticsLipopolysaccharides/pharmacologyLiver/drug effects/immunology/pathologyLung/drug effects/immunology/pathologyLymphocyte Antigen 96/blood/secretionMaleMiddle AgedSepsis/blood/immunology/metabolismSolubility/drug effectsTumor Necrosis Factor-alpha/pharmacology
PMID: 18384879
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Research group Groupe Pugin Jérôme (Soins intensifs) (587)
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WOLFS, Tim G.A.M. et al. Increased release of sMD-2 during human endotoxemia and sepsis: a role for endothelial cells. In: Molecular Immunology, 2008, vol. 45, n° 11, p. 3268-77. doi: 10.1016/j.molimm.2008.02.014 https://archive-ouverte.unige.ch/unige:2171

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Deposited on : 2009-06-26

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