IL‐25 prevents and cures fulminant hepatitis in mice through a myeloid‐derived suppressor cell‐dependent mechanism. Issue 4 (26th August 2013)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Hepatology. Volume 58:Issue 4(2013:Oct.)
• Page Start: 1436
• Page End: 1450
• Publication Date: 2013-08-26
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.26446
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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<sup>+</sup>CD11b<sup>+</sup> cells. CFSE‐labeled T cells were cocultured with GR1<sup>+</sup>CD11b<sup>+</sup> 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. <italic>In vitro</italic> studies showed that GR1<sup>+</sup>CD11b<sup>+</sup> cells isolated from mice given IL‐25 inhibited T‐cell proliferation. Consistently, <italic>in vivo</italic> depletion of GR1<sup>+</sup> 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. <italic>Conclusions</italic>: IL‐25 expression is markedly reduced during human and experimental FH. IL‐25 promotes liver accumulation of GR1<sup>+</sup>CD11b<sup>+</sup>cells with immunoregulatory properties. (H<sc>epatology</sc> 2013;58:1436–1450)</p> </abstract>