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Inhibition of colitis by IL-25 associates with induction of alternatively activated macrophages

Rizzo, Angelamaria MD1; Monteleone, Ivan MD1; Fina, Daniele MD1; Stolfi, Carmine PhD1; Caruso, Roberta MD1; Fantini, Massimo Claudio MD1; Franzè, Eleonora PhD1; Schwendener, Reto MD2; Pallone, Francesco MD1; Monteleone, Giovanni MD1,*

doi: 10.1002/ibd.21799
Original Article

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. (Inflamm Bowel Dis 2012;)

1 Department of Internal Medicine, University “Tor Vergata” of Rome, Rome, Italy

2 Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland

* Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy

Email: Gi.Monteleone@Med.uniroma2.it

Received 28 April 2011; Accepted 19 May 2011

Published online 17 June 2011 in Wiley Online Library (wileyonlinelibrary.com).

Supported by the “Fondazione Umberto di Mario,” Rome, the Broad Medical Research Program Foundation (No. IBD-0242), and Giuliani SpA, Milan, Italy.

Declaration: G.M. has filed a patent entitled “A treatment for inflammatory diseases”“ (patent No. 08154101.3), while the remaining authors have no conflicts of interest to disclose.

© Crohn's & Colitis Foundation of America, Inc.
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