Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock.
In this paper, we show that plasma from patients with severe sepsis and septic shock but not normal plasma supports lipopolysaccharide (LPS) activation of epithelial cells expressing Toll-like receptor 4 (TLR4). Recombinant soluble myeloid differentiation protein-2 (MD-2) complemented normal plasma and allowed LPS activation of epithelial cells to levels measured with "septic" plasma, whereas soluble MD-2-depleted plasma lost its effects. The same "MD-2 activity" was found in urine from a patient with septic shock and in lung edema fluids from patients with adult respiratory distress syndrome (ARDS). Recombinant soluble MD-2 enabled LPS-dependent activation of epithelial cells bearing TLR4. LPS-binding protein (LBP) and soluble CD14 increased the sensitivity of TLR4-expressing epithelial cells to LPS but were not able to mediate LPS activation of these cells in the absence of soluble MD-2. An anti-MD-2 monoclonal antibody blocked LPS activation of TLR4-expressing cells only in the presence of septic plasma or septic urine. These results suggest that septic plasma containing soluble MD-2 leaking into the extravascular space supports LPS activation of TLR4-expressing epithelial cells. We therefore propose that soluble MD-2 is an important mediator of organ inflammation during sepsis.
Laboratory of the Division of Intensive Care, Department of Internal Medicine, University Hospital of Geneva, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. jerome.pugin@medecine.unige.ch
Jérôme
J
Pugin
Sabine
S
Stern-Voeffray
Bruno
B
Daubeuf
Michael A
MA
Matthay
Greg
G
Elson
Irène
I
Dunn-Siegrist
D000954:Antigens, Surface / Q000097:blood* / Q000235:genetics / Q000652:urine; D002352:Carrier Proteins / Q000097:blood* / Q000235:genetics / Q000652:urine; D002460:Cell Line; D017931:DNA Primers; D004730:Endothelium, Vascular / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007668:Kidney; D008070:Lipopolysaccharides / Q000276:immunology; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins / Q000097:blood / Q000235:genetics / Q000276:immunology; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000097:blood / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D018805:Sepsis / Q000097:blood* / Q000276:immunology; D012772:Shock, Septic / Q000097:blood* / Q000276:immunology; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D000954:Antigens, Surface; D002352:Carrier Proteins; D017931:DNA Primers; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors