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
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.