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

doi:10.1016/j.molimm.2008.02.014

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-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 language	English
Pages (from-to)	3268-3277
Journal	Molecular Immunology
Volume	45
Issue number	11
DOIs	https://doi.org/10.1016/j.molimm.2008.02.014
Publication status	Published - 1 Jan 2008

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10.1016/j.molimm.2008.02.014

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@article{516176de2c114edfb3588440e934c42d,

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

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",

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

year = "2008",

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doi = "10.1016/j.molimm.2008.02.014",

language = "English",

volume = "45",

pages = "3268--3277",

journal = "Molecular Immunology",

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number = "11",

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TY - JOUR

T1 - Increased release of sMD-2 during human endotoxemia and sepsis: a role for endothelial cells.

AU - Wolfs, T.G.

AU - Dunn-Siegrist, I.

AU - van 't Veer, C.

AU - Hodin, C.M.

AU - Germeraad, W.T.V.

AU - van Zoelen, M.

AU - van Suylen, R.J.

AU - Peutz-Kootstra, C.J.

AU - Elson, G.

AU - Pugin, J.

AU - Buurman, W.A.

PY - 2008/1/1

Y1 - 2008/1/1

N2 - 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

AB - 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

U2 - 10.1016/j.molimm.2008.02.014

DO - 10.1016/j.molimm.2008.02.014

M3 - Article

C2 - 18384879

SN - 0161-5890

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SP - 3268

EP - 3277

JO - Molecular Immunology

JF - Molecular Immunology

IS - 11

ER -