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

The Journal of Immunology : Official Journal of the American Association of Immunologists
Céline LamacchiaC Gabay

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 p...Continue Reading

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Citations

May 6, 2011·Science Translational Medicine·Seth L MastersLuke A J O'Neill
Feb 1, 2011·American Journal of Respiratory and Critical Care Medicine·Susanne HeroldJuergen Lohmeyer
Nov 28, 2015·Biomarkers in Medicine·Tim HendrikxRonit Shiri-Sverdlov
Feb 27, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Praxedis MartinCem Gabay
Dec 17, 2017·Immunological Reviews·Martina MolgoraCecilia Garlanda
Apr 28, 2012·European Journal of Immunology·Céline LamacchiaCem Gabay
Nov 26, 2013·International Journal of Geriatric Psychiatry·Francis E LotrichAriel G Gildengers
Jan 15, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Praxedis MartinCem Gabay
Sep 13, 2014·PloS One·Kimberly A NegrinMichael P Czech

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