Distinct roles of hepatocyte- and myeloid cell-derived IL-1 receptor antagonist during endotoxemia and sterile inflammation in mice.
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.
Lamacchia
Céline
C
Division of Rheumatology, University Hospitals of Geneva, Geneva, Switzerland.
Palmer
Gaby
G
Bischoff
Loraine
L
Rodriguez
Emiliana
E
Talabot-Ayer
Dominique
D
Gabay
Cem
C
D000209:Acute-Phase Proteins / Q000235:genetics / Q000502:physiology; D000818:Animals; D019446:Endotoxemia / Q000097:blood* / Q000503:physiopathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D007150:Immunohistochemistry; D007249:Inflammation / Q000097:blood* / Q000139:chemically induced / Q000503:physiopathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood* / Q000235:genetics / Q000502:physiology; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D016019:Survival Analysis
D000209:Acute-Phase Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides