title: Inhibition of colitis by IL-25 associates with induction of alternatively activated macrophages.
abstract: BACKGROUND
  Interleukin (IL)-25, a Th2-related factor, inhibits the synthesis of inflammatory cytokines by macrophages and attenuates experimental colitis in mice. The mechanism underlying the counterregulatory effect of IL-25, however, remains unknown. Since Th2-cytokines can abrogate inflammatory pathways by inducing alternatively activated macrophages (AAMs), we evaluated whether AAMs are involved in the IL-25-mediated anticolitic effect.
  
  
  METHODS
  AAM-related markers were evaluated in peritoneal and lamina propria mononuclear cells of mice with or without 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced colitis treated with IL-25 and/or neutralizing IL-4, IL-13, and transforming growth factor beta 1 (TGF-β1) antibodies. Peritoneal AAMs induced in vivo by injecting mice with IL-25 were transferred to mice with TNBS colitis. Finally, we assessed the in vitro effect of IL-25 on the alternative activation of peritoneal F4/80+ cells.
  
  
  RESULTS
  IL-25 enhanced the expression of AAM-related markers in F4/80(+) cells infiltrating the peritoneum and colon of naïve and colitic mice. Peritoneal F4/80(+) cells isolated from IL-25-treated mice reduced the severity of TNBS colitis when injected intraperitoneally to recipient mice. Since IL-25 did not directly induce AAM in vitro and in vivo in mice, IL-25 administration enhanced the expression of IL-4, IL-13, and TGF-β1, which are known to promote AAM differentiation, we finally assessed whether such cytokines were involved in the IL-25-driven AAM induction. Blockade of IL-4, IL-13, and TGF-β1 with neutralizing antibodies in mice did not inhibit the stimulatory effect of IL-25 on AAM gene expression.
  
  
  CONCLUSIONS
  The IL-25-mediated anticolitic effect is associated with induction of AAMs, a subset of macrophages with antiinflammatory properties.
authors.affiliation: Department of Internal Medicine, University Tor Vergata of Rome, Rome, Italy. Gi.Monteleone@Med.uniroma2.it
authors.forename: Angelamaria
authors.initials: A
authors.lastname: Rizzo
authors.forename: Ivan
authors.initials: I
authors.lastname: Monteleone
authors.forename: Daniele
authors.initials: D
authors.lastname: Fina
authors.forename: Carmine
authors.initials: C
authors.lastname: Stolfi
authors.forename: Roberta
authors.initials: R
authors.lastname: Caruso
authors.forename: Massimo Claudio
authors.initials: MC
authors.lastname: Fantini
authors.forename: Eleonora
authors.initials: E
authors.lastname: Franzè
authors.forename: Reto
authors.initials: R
authors.lastname: Schwendener
authors.forename: Francesco
authors.initials: F
authors.lastname: Pallone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000943:Antigens, Differentiation / Q000378:metabolism; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D015870:Gene Expression; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology* / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism; D037102:Lectins / Q000235:genetics / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018709:Statistics, Nonparametric; D016212:Transforming Growth Factor beta / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D000943:Antigens, Differentiation; D036341:Intercellular Signaling Peptides and Proteins; D018793:Interleukin-13; D020381:Interleukin-17; D037102:Lectins; C413576:Retnla protein, mouse; D016212:Transforming Growth Factor beta; C036763:monocyte-macrophage differentiation antigen; D015847:Interleukin-4; D014302:Trinitrobenzenesulfonic Acid; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases; C544448:Arg1 protein, mouse; D001119:Arginase