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Innate Immunity
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The effect of systemic iNOS inhibition during human endotoxemia on the development of tolerance to different TLR-stimuli

Annelies Draisma

Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Mirrin Dorresteijn

Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre

Peter Pickkers

Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, p.pickkers{at}ic.umcn.nl

Hans van der Hoeven

Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, Nijmegen University Centre for Infectious Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

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.

Key Words: Aminoguanidine • endotoxin tolerance • human • inducible NO-synthase • Toll-like receptors

Innate Immunity, Vol. 14, No. 3, 153-159 (2008)
DOI: 10.1177/1753425908091959
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