A cyanobacterial lipopolysaccharide antagonist inhibits cytokine production induced by Neisseria meningitidis in a human whole-blood model of septicemia.
Septicemia caused by Neisseria meningitidis is characterized by increasing levels of meningococcal lipopolysaccharide (Nm-LPS) and cytokine production in the blood. We have used an in vitro human whole-blood model of meningococcal septicemia to investigate the potential of CyP, a selective Toll-like receptor 4 (TLR4)-MD-2 antagonist derived from the cyanobacterium Oscillatoria planktothrix FP1, for reducing LPS-mediated cytokine production. CyP (> or = 1 microg/ml) inhibited the secretion of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-6 (by >90%) and chemokines IL-8 and monocyte chemoattractant protein 1 (by approximately 50%) induced by the treatment of blood with pure Nm-LPS, by isolated outer membranes, and after infection with live meningococci of different serogroups. In vitro studies with human dendritic cells and TLR4-transfected Jurkat cells demonstrated that CyP competitively inhibited Nm-LPS interactions with TLR4 and subsequent NF-kappaB activation. These data demonstrate that CyP is a potent antagonist of meningococcal LPS and could be considered a new adjunctive therapy for treating septicemia.
Jemmett
Kim
K
Neisseria Research Group, Molecular Microbiology, Division of Infection, Inflammation and Repair, University of Southampton Medical School, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.
Macagno
Annalisa
A
Molteni
Monica
M
Heckels
John E
JE
Rossetti
Carlo
C
Christodoulides
Myron
M
D016470:Bacteremia / Q000276:immunology* / Q000382:microbiology; D000458:Cyanobacteria / Q000276:immunology*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D003713:Dendritic Cells; D006801:Humans; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009345:Neisseria meningitidis / Q000472:pathogenicity*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection
D016207:Cytokines; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4