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Distinct roles of hepatocyte- and myeloid cell-derived IL-1 receptor antagonist during endotoxemia and sterile inflammation in mice

Talabot-Ayer, Dominique
Published in Journal of Immunology. 2010, vol. 185, no. 4, p. 2516-2524
Abstract IL-1R antagonist (IL-1Ra) is a natural inhibitor of the pleiotropic proinflammatory activities of IL-1. Although several reports described the effects of complete IL-1Ra deficiency, no study has examined the consequences of cell type-specific IL-1Ra inactivation during systemic inflammation. Previous in vitro data demonstrated high IL-1Ra production by hepatocytes and myeloid cells after endotoxin stimulation. In addition, hepatocyte IL-1Ra production is regulated as an acute-phase protein in vitro. In this study, we analyzed the production and functional role of hepatocyte- and myeloid cell-derived IL-1Ra during endotoxin-induced septic shock and acute IL-1beta-induced sterile inflammation. Using conditional IL-1Ra knockout mice, we showed that hepatocytes and myeloid cells are the two major cellular sources of circulating IL-1Ra in response to LPS. Interestingly, IL-1Ra production by myeloid cells, but not hepatocytes, is critical for survival during endotoxemia. Furthermore, we provide the first in vivo evidence demonstrating that IL-1Ra is produced as an acute-phase protein by hepatocytes during IL-1beta-induced inflammation and that hepatocyte-derived IL-1Ra functions as an endogenous negative feedback downregulating the proinflammatory effects of IL-1. Taken together, our observations define distinct roles for two major cellular sources of IL-1Ra in response to different types of systemic inflammatory stimuli in vivo.
Keywords Acute-Phase Proteins/genetics/physiologyAnimalsEndotoxemia/*blood/physiopathologyEnzyme-Linked Immunosorbent AssayFemaleHepatocytes/*metabolismImmunohistochemistryInflammation/*blood/chemically induced/physiopathologyInterleukin 1 Receptor Antagonist Protein/*blood/genetics/physiologyLipopolysaccharidesLiver/metabolismLung/metabolismMaleMiceMice, Inbred C57BLMice, KnockoutMyeloid Cells/*metabolismSpleen/metabolismSurvival Analysis
PMID: 20639493
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Other version: http://www.jimmunol.org/content/185/4/2516.full.pdf
Research group Mécanisme de l'inflammation articulaire (44)
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LAMACCHIA, Céline et al. Distinct roles of hepatocyte- and myeloid cell-derived IL-1 receptor antagonist during endotoxemia and sterile inflammation in mice. In: Journal of Immunology, 2010, vol. 185, n° 4, p. 2516-2524. doi: 10.4049/jimmunol.1000872 https://archive-ouverte.unige.ch/unige:21063

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Deposited on : 2012-05-23

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