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Infection and Immunity, July 2008, p. 3156-3163, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.00110-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

A Cyanobacterial Lipopolysaccharide Antagonist Inhibits Cytokine Production Induced by Neisseria meningitidis in a Human Whole-Blood Model of Septicemia

Neisseria Research Group, Molecular Microbiology, Division of Infection, Inflammation and Repair, University of Southampton Medical School, Southampton General Hospital, Southampton SO16 6YD, United Kingdom,¹ Institute for Research in Biomedicine, Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland,² Department of Biotechnology and Molecular Sciences, University of Insubria, Via Dunant 3, 21100 Varese, Italy³

Received 25 January 2008/ Returned for modification 11 March 2008/ Accepted 17 April 2008

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 (1 µg/ml) inhibited the secretion of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1β (IL-1β), and IL-6 (by >90%) and chemokines IL-8 and monocyte chemoattractant protein 1 (by 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-B activation. These data demonstrate that CyP is a potent antagonist of meningococcal LPS and could be considered a new adjunctive therapy for treating septicemia.

Published ahead of print on 28 April 2008.

Editor: J. N. Weiser