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

Article Article scientifique Article Distinct roles of hepatocyte- and myeloid cell-derived IL-1 receptor antagonist during endotoxemia and sterile inflammation in mice eng 2010 author Lamacchia Céline 629219 author Palmer-Lourenco Gaby 0000-0001-7567-1798 45743 author Bischoff Loraine 517508 author Rodriguez Emiliana 583750 author Talabot-Ayer Dominique author Gabay Cem 70978 2516-2524 10.4049/jimmunol.1000872 20639493 0022-1767 http://www.jimmunol.org/content/185/4/2516.full.pdf 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. Acute-Phase Proteins/genetics/physiology Animals Endotoxemia/blood/physiopathology Enzyme-Linked Immunosorbent Assay Female Hepatocytes/metabolism Immunohistochemistry Inflammation/blood/chemically induced/physiopathology Interleukin 1 Receptor Antagonist Protein/blood/genetics/physiology Lipopolysaccharides Liver/metabolism Lung/metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Myeloid Cells/metabolism Spleen/metabolism Survival Analysis Dewey 616 56 Département de médecine 221 false 28 Inflammation articulaire 44 The Journal of immunology 185 4 435a6d10-0dc5-468d-975c-889c44f9d484 Article (Published version) Restricted file1.pdf 1203312 application/pdf restrictedAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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Distinct roles of hepatocyte- and myeloid cell-derived IL-1 receptor antagonist during endotoxemia and sterile inflammation in mice	The Journal of immunology			2010	577	0

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