title: Mice deficient in hepatocyte-specific IL-1Ra show delayed resolution of concanavalin A-induced hepatitis.
abstract: Interleukin-1 receptor antagonist (IL-1Ra) is a specific IL-1 inhibitor that possesses anti-inflammatory activities. Several studies in human and mouse suggested a protective role for IL-1Ra in liver inflammation, and we previously demonstrated that hepatocytes produce high levels of IL-1Ra in response to inflammatory challenge in vitro and in vivo. In the present study, we investigated the production and the biological function of hepatocyte-derived IL-1Ra in concanavalin A (ConA)-induced hepatitis in mice. We show that the injured liver produces large amounts of IL-1Ra and that secreted and intracellular IL-1Ra isoforms are produced with different kinetics during the course of hepatitis. By using hepatocyte-specific IL-1Ra-deficient mice (IL-1Ra(ΔH)), we demonstrate that hepatocytes represent the major cellular source of local IL-1Ra. Most interestingly, hepatic necrosis and inflammation were increased in IL-1Ra(ΔH) as compared with wild-type mice during the late phase of the disease, leading to a delayed resolution of hepatitis in IL-1Ra(ΔH) mice. In conclusion, our results show that the local production of IL-1Ra by hepatocytes contributes to the resolution of hepatitis.
authors.affiliation: Division of Rheumatology, University Hospital and Department of Pathology and Immunology, University of Geneva School of Medicine, Geneva, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Lamacchia
authors.forename: Emiliana
authors.initials: E
authors.lastname: Rodriguez
authors.forename: Gaby
authors.initials: G
authors.lastname: Palmer
authors.forename: Christian
authors.initials: C
authors.lastname: Vesin
authors.forename: Christian A
authors.initials: CA
authors.lastname: Seemayer
authors.forename: Laura
authors.initials: L
authors.lastname: Rubbia-Brandt
authors.forename: Cem
authors.initials: C
authors.lastname: Gabay
mesh_terms: D000818:Animals; D003208:Concanavalin A / Q000633:toxicity; D016207:Cytokines / Q000032:analysis; D006505:Hepatitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000276:immunology
chemical_list: D016207:Cytokines; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D003208:Concanavalin A