Increased release of sMD-2 during human endotoxemia and sepsis: a role for endothelial cells.
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.
Wolfs
Tim G A M
TG
Department of Surgery, Nutrition and Toxicology Research Institute Maastricht, Academic Hospital Maastricht and Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands.
Dunn-Siegrist
Irène
I
van't Veer
Cornelis
C
Hodin
Caroline M I M
CM
Germeraad
Wilfred T V
WT
van Zoelen
Marieke A D
MA
van Suylen
Robert-Jan
RJ
Peutz-Kootstra
Carine J
CJ
Elson
Greg
G
Pugin
Jérôme
J
Buurman
Wim A
WA
D000328:Adult; D016022:Case-Control Studies; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019446:Endotoxemia / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006413:Hematopoietic System / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051218:Lymphocyte Antigen 96 / Q000097:blood / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018805:Sepsis / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D012995:Solubility / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D014409:Tumor Necrosis Factor-alpha