| First Author | Lamacchia C | Year | 2010 |
| Journal | J Immunol | Volume | 185 |
| Issue | 4 | Pages | 2516-24 |
| PubMed ID | 20639493 | Mgi Jnum | J:162537 |
| Mgi Id | MGI:4819288 | Doi | 10.4049/jimmunol.1000872 |
| Citation | Lamacchia C, et al. (2010) Distinct Roles of Hepatocyte- and Myeloid Cell-Derived IL-1 Receptor Antagonist during Endotoxemia and Sterile Inflammation in Mice. J Immunol 185(4):2516-24 |
| abstractText | 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. |
