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Induction of IRAK-M Is Associated with Lipopolysaccharide Tolerance in a Human Endotoxemia Model

Cornelis van ‘t Veer^1,*,, Petra S. van den Pangaart^*,, Marieke A. D. van Zoelen^*,, Martijn de Kruif^*,, Rakesh S. Birjmohun, Eric S. Stroes, Alex F. de Vos^*, and Tom van der Poll^*,

^* Center for Infection and Immunity Amsterdam, Center for Experimental and Molecular Medicine, and Department of Vascular Medicine, University of Amsterdam, Amsterdam, The Netherlands

Recent in vitro and murine in vivo studies have identified several potential LPS tolerance factors. In this study, we describe the expression kinetics of these LPS tolerance factors in standardized human endotoxemia models using i.v. LPS bolus administration. Responsiveness to LPS as well as the expression of potential regulators of LPS signaling were determined in peripheral whole blood. Intravenous LPS administration (4 ng/kg) resulted in peak plasma levels of TNF- at 1.5 h followed by subsequent peaks of the classic negative feedback inhibitors A20 and IL-10 at 2 and 3 h, respectively. Circulating blood monocyte counts decimated during the initial inflammatory response, but normalized in the period between 4 and 8 h post-LPS. The LPS response as determined by ex vivo TNF release per monocyte in whole blood was profoundly decreased at 6–8 h post-LPS injection despite cessation of A20 and IL-10 expression after 4 h. Analysis of MyD88short, IL-1R-associated kinase (IRAK)-1, IRAK-M, ST2, suppressor of cytokine signaling-1 and -3, SHIP-1, and MAP kinase phosphatase-1 expression indicated that the observed LPS tolerance was associated with decreased IRAK-1 and elevated IRAK-M expression in this human model. Interestingly, a lower dose of LPS (1 ng/kg) induced LPS tolerance accompanied with IRAK-M up-regulation but without depletion of IRAK-1. In vitro studies in whole blood showed that IRAK-M up-regulation by LPS is largely dependent on TNF-. The observed rise of IRAK-M transcription in the human endotoxemia model appeared much greater compared with in vitro-stimulated whole blood. In conclusion, LPS tolerance in human endotoxemia models is associated with IRAK-M up-regulation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Cornelis van ‘t Veer, Center for Experimental and Molecular Medicine, G2-131, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: c.vantveer{at}amc.uva.nl

² Abbreviations used in this paper: IRAK, IL-1R-associated kinase; TRAF, TNFR-associated factor; IKK, IB kinase; SOCS, suppressor of cytokine signaling; TAK₁, transforming growth factor-β-activated kinase; TRIF, TIR domain containing adaptor inducing IFN-β; TRAM, TRIF-related adaptor molecule; MKP-1, MAP kinase phosphatase 1.

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