8th Annual BMRP Investigator Meeting - Abstract
Antagonistic Effects of Interleukin-25 on CD14+ Cell Cytokine Responses in the Gut
Roberta Carusob, Ivan Monteleone, AngelaMaria Rizzo, Carmine Stolfi, Daniele Fina, Massimiliano Sarra, Massimo Claudio Fantini and Giovanni Monteleonea
Department of Internal Medicine, University Tor Vergata of Rome (Italy)
Defects in counter-regulatory mechanisms are believed to play a major role in the pathogenesis of inflammatory bowel diseases (IBD). Interleukin (IL)-25, a member of the IL-17 family, is able to expand Th2 cell responses, as well as to negatively regulate the development and/or amplification of Th17-mediated pathology. These findings raise the possibility that IL-25 may either promote or inhibit specific inflammatory responses. To assess the role of IL-25 in IBD, we first evaluated the expression of IL-25 in colonic biopsies taken from patients with IBD, and normal controls. Patients with Crohn’s disease or ulcerative colitis produced significantly less IL-25 compared to controls. By contrast, high IL-25 expression was seen in the gut of patients with active celiac disease, thus indicating that the defective synthesis of IL-25 in IBD is not an epiphenomenon of the ongoing inflammation. Among inflammatory cytokines, only TNF-alpha was able to reduce IL-25 production in ex vivo organ cultures of normal mucosal explants. Consistently, anti-TNF-alpha enhanced IL-25 expression both in vitro and in vivo. We also showed that TGF-beta1 but not IL-10 did increase IL-25 expression in the gut. Second, we demonstrated that mucosal CD14+ cells express high levels of IL-25 receptor and respond to IL-25 by down-regulating the production of multiple inflammatory cytokines. Consistently, in vivo in mice, administration of IL-25 prevented and cured experimental colitis, through a mechanism that appeared to be IL-13-independent. Overall these data suggest that, in IBD, a defective production of IL-25 can contribute to sustain the pathogenic response and that IL-25-based therapy could be a promising approach for the management of IBD patients.
aPrincipal Investigator; bCo-Investigator and Presenter