The effect of systemic iNOS inhibition during human endotoxemia on the development of tolerance to different TLR-stimuli.
The phenomenon of repeated exposure to endotoxin resulting in diminished release of pro-inflammatory cytokines is called endotoxin tolerance, in which there is a putative role for nitric oxide (NO). We investigated the effect of selective inducible NO-synthase (iNOS) inhibition during experimental human endotoxemia on the development of tolerance to various Toll-like receptor (TLR) agonists ex vivo. Volunteers received 2 ng/kg Escherichia coli endotoxin in the absence (n = 7) or presence (n = 7) of the selective iNOS inhibitor aminoguanidine (bolus 5 mM followed by a continuous infusion of 1.5 mmol/h). At 0, 2 and 4 h, blood samples were drawn for ex vivo stimulation with different TLR agonists. Experimental endotoxemia did not induce tolerance to TLR-2 and TLR-7 stimulation. In TLR-3, TLR-4 and TLR-5 stimulated whole blood, pro- and anti-inflammatory cytokine release was attenuated at 4 h, indicating that endotoxin-induced tolerance is not confined to subsequent TLR-4 stimulation alone. Aminoguanidine-treated subjects also developed tolerance to TLR-4 stimulation. In contrast, tolerance to TLR-3 stimulation did not occur for IL-10, and tolerance in TLR-5 stimulated blood did not develop for both pro- and anti-inflammatory cytokines. The role of NO in the development of tolerance is different for the various TLRs stimulated and pro- and anti-inflammatory cytokines measured.
Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Annelies
A
Draisma
Mirrin
M
Dorresteijn
Peter
P
Pickkers
Hans
H
van der Hoeven
D000328:Adult; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood; D019446:Endotoxemia / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000097:blood; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*
D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D052247:Nitric Oxide Synthase Type II