Identification of lipopolysaccharide binding site on high molecular weight kininogen.
Plasma kallikrein kinin system (KKS) activation along with its cellular receptors expression are increased after injury and in patients with septic shock, hypotensive bacteremia and rhesus monkey infected with Salmonella typhimurium. KKS signaling cascade is activated by activated factor XII (FXIIa, Hageman factor)- and prolylcarboxypeptidase (PRCP)-dependent pathways on endothelial cells. Among the many entities that comprise the KKS, high molecular weight kininogen (HK), a bradykinin precursor, is critical in the assembly and activation of this system. HK is primarily expressed in the liver and secreted into the bloodstream. The activation of the KKS influences the permeability of the endothelium by liberating bradykinin (BK) from HK. BK is a potent inflammatory peptide which stimulates constitutive bradykinin B2 and inducible B1 receptors to release nitric oxide and prostacyclin. Regardless of the triggers, PK can only be activated on HK bound to the artificial negatively charged or to cell membrane surfaces. Since LPS has a negatively charged moiety and the ability to induce inflammatory responses in human, we determined the interaction between LPS and HK. HKH19 (HK cell binding site) and heparin inhibited LPS binding to HK with IC(50)s of 15nM and 20 microg/ml, respectively. C1-inhibitor and N-acetylglucosamine glycan inhibited LPS binding to HK with IC(50)s of about 10 microg/ml and 10mM, respectively. This novel study underscores the implication of HK in infection. We propose that HKH19, heparin, and C1-inhibitor present therapeutic potential for the treatment of sepsis and hypotensive bacteremia.
Perkins
R
R
The School of Pharmacy, Department of Pharmacology, University of Mississippi, 317 Faser Hall University, MS 38677-1848, USA.
Ngo
M Dinh
MD
Mahdi
F
F
Shariat-Madar
Z
Z
D001665:Binding Sites; D001710:Biotin / Q000378:metabolism; D019921:Biotinylation; D002241:Carbohydrates / Q000494:pharmacology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D019679:Kininogen, High-Molecular-Weight / Q000737:chemistry* / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D009994:Osmolar Concentration; D013997:Time Factors; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D002241:Carbohydrates; D019679:Kininogen, High-Molecular-Weight; D008070:Lipopolysaccharides; D001710:Biotin; D006493:Heparin