RRR schreef op 27 mei 2012 15:59:
C1-Inhibitor Suppresses the Endotoxic Activity of a Wide Range of Lipopolysaccharides and Interacts With Live Gram-Negative Bacteria
Human C1-Inhibitor (C1INH) prevents endotoxin shock via a direct interaction with Gram-negative bacterial lipopolysaccharide (LPS) and improves survival in animal models of sepsis. In this report we further characterize the interaction of C1INH with LPS and whole live bacteria. We investigate C1INH interactions with LPS from five different strains of Gram-negative enteric bacteria known to participate in the pathogenesis of human sepsis. Treatment with C1INH improved survival in mice with endotoxin shock induced by LPS from Salmonella enterica serovar Typhimurium as previously shown, as well as LPS from Escherichia coli O55:B5 (EcLPS) and Pseudomonas aeruginosa (PaLPS), and a trend to improved survival was observed when Klebsiella pneumoniae (KpLPS) and Serratia marcescens (SmLPS) LPS were used. ELISA and native PAGE shift experiments demonstrated a direct interaction of C1INH with LPS from all the strains studied. The binding of both native and reactive center cleaved, inactive C1INH results in inhibition of LPS-induced pro-inflammatory cytokine production. Furthermore, we demonstrate the ability of C1INH to bind at the surface of only a restricted number of whole live Gram-negative bacteria as well as mutant bacteria expressing a truncated LPS lacking the O-antigen. These data reveal the interaction of C1INH with a wide range of enteric bacterial LPS and strongly suggest that the interaction between C1INH and the surface of Gram-negative microorganisms is determined by the length of the polysaccharide chain of the endotoxin molecule.