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IL‐25 prevents and cures fulminant hepatitis in mice through a myeloid‐derived suppressor cell‐dependent mechanism
Author(s) -
Sarra Massimiliano,
Cupi Maria Laura,
Bernardini Roberta,
Ronchetti Giulia,
Monteleone Ivan,
Ranalli Marco,
Franzè Eleonora,
Rizzo Angelamaria,
Colantoni Alfredo,
Caprioli Flavio,
Maggioni Marco,
Gambacurta Alessandra,
Mattei Maurizio,
Macdonald Thomas T.,
Pallone Francesco,
Monteleone Giovanni
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26446
Subject(s) - lipopolysaccharide , integrin alpha m , concanavalin a , fulminant hepatitis , immunology , chemistry , microbiology and biotechnology , biology , flow cytometry , in vitro , hepatitis , biochemistry
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. (H epatology 2013;58:1436–1450)