Induction of IRAK-M is associated with lipopolysaccharide tolerance in a human endotoxemia model.
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-alpha 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-alpha. 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.
van 't Veer
Cornelis
C
Center for Infection and Immunity Amsterdam, The Netherland. c.vantveer@amc.uva.nl
van den Pangaart
Petra S
PS
van Zoelen
Marieke A D
MA
de Kruif
Martijn
M
Birjmohun
Rakesh S
RS
Stroes
Eric S
ES
de Vos
Alex F
AF
van der Poll
Tom
T
D004268:DNA-Binding Proteins; D004306:Dose-Response Relationship, Immunologic; D054638:Dual Specificity Phosphatase 1 / Q000276:immunology / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D000072181:Inositol Polyphosphate 5-Phosphatases; D053592:Interleukin-1 Receptor-Associated Kinases / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D000072179:Interleukin-1 Receptor-Like 1 Protein; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity*; D008297:Male; D018448:Models, Immunological; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D004268:DNA-Binding Proteins; C508609:IL10 protein, human; C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D009687:Nuclear Proteins; D011956:Receptors, Cell Surface; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C507768:IRAK1 protein, human; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D010744:Phosphoric Monoester Hydrolases; D054638:Dual Specificity Phosphatase 1; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3