title: IL-25 prevents and cures fulminant hepatitis in mice through a myeloid-derived suppressor cell-dependent mechanism.
abstract: Fulminant hepatitis (FH) is a disease characterized by massive destruction of hepatocytes with severe impairment of liver function. The pathogenesis of FH is not fully understood, but hyperactivity of T cells and macrophages with excessive production of cytokines are important hallmarks of the condition. In this study, we investigated the role of interleukin (IL)-25 in FH. IL-25 expression was evaluated in patients with FH and in livers of mice with FH induced by D-galactosamine (D-Gal) and lipopolysaccharide (LPS). Mice were treated with IL-25 before D-Gal/LPS-induced FH and before or after concanavalin A (ConA)-induced FH. Mononuclear cells were isolated from livers of mice treated with or without IL-25 and analyzed for GR1(+) CD11b(+) cells. CFSE-labeled T cells were cocultured with GR1(+) CD11b(+) cells and their proliferation was evaluated by flow cytometry. Mice were also treated with a depleting anti-GR1 antibody before IL-25 and D-Gal/LPS administration. IL-25 was constitutively expressed in mouse and human liver and down-regulated during FH. IL-25 prevented D-Gal/LPS-induced FH and this effect was associated with increased infiltration of the liver with cells coexpressing GR1 and CD11b. In vitro studies showed that GR1(+) CD11b(+) cells isolated from mice given IL-25 inhibited T-cell proliferation. Consistently, in vivo depletion of GR1(+) cells abrogated the protective effect of IL-25 in experimental D-Gal/LPS-induced FH. IL-25 was both preventive and therapeutic in ConA-induced FH.
  
  
  CONCLUSIONS
  IL-25 expression is markedly reduced during human and experimental FH. IL-25 promotes liver accumulation of GR1(+) CD11b(+) cells with immunoregulatory properties.
authors.affiliation: Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Sarra
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Cupi
authors.forename: Roberta
authors.initials: R
authors.lastname: Bernardini
authors.forename: Giulia
authors.initials: G
authors.lastname: Ronchetti
authors.forename: Ivan
authors.initials: I
authors.lastname: Monteleone
authors.forename: Marco
authors.initials: M
authors.lastname: Ranalli
authors.forename: Eleonora
authors.initials: E
authors.lastname: Franzè
authors.forename: Angelamaria
authors.initials: A
authors.lastname: Rizzo
authors.forename: Alfredo
authors.initials: A
authors.lastname: Colantoni
authors.forename: Flavio
authors.initials: F
authors.lastname: Caprioli
authors.forename: Marco
authors.initials: M
authors.lastname: Maggioni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gambacurta
authors.forename: Maurizio
authors.initials: M
authors.lastname: Mattei
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Macdonald
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D018920:Coculture Techniques; D003208:Concanavalin A / Q000009:adverse effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005688:Galactosamine / Q000009:adverse effects; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D019707:Receptors, Chemokine / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
chemical_list: D039481:CD11b Antigen; C503133:Gr-1 protein, mouse; C486701:IL25 protein, human; D020381:Interleukin-17; D007378:Interleukins; D008070:Lipopolysaccharides; C442281:Mydgf protein, mouse; D019707:Receptors, Chemokine; D003208:Concanavalin A; D005688:Galactosamine