Scientific Abstract

Proposal No. IBD-0242
Principal Investigator:   Giovanni Monteleone, M.D., Ph.D.
Applicant Organization:  University of Rome "Tor Vergata" (Italy)
Project Title:  Antagonistic effects of interleukin-25 on CD14+ cell cytokine responses in the gut
Period of Award:  June 1, 2008 – June 30, 2010

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract that share clinical and pathological characteristics. The most accredited hypothesis is that both CD and UC result from a deregulated mucosal immune response to normal constituents of the gut microflora. Evidence however indicates that CD and UC are immunologically different diseases, even though they share end-stage effector pathways of tissue damage. For example, in the intestinal tissue of patients with CD and patients with UC, there is enhanced production of cytokines that amplify and sustain the ongoing mucosal inflammation. These advances led to the development of novel therapeutic agents that are currently being studied for their capacity to specifically target the mucosal inflammatory pathways occurring in such patients.

Interleukin (IL)-25 (also known as IL-17E) is a member of the IL-17 family. Although initially identified as a factor that regulates T cell functions and expands Th2 cell responses, IL-25 has been subsequently reported to control the activity of other cell types. For example, studies in murine models of autoimmunity have shown that IL-25 can negatively regulate the development and/or amplification of Th17-mediated pathology, raising the possibility that IL-25 may either promote or inhibit specific inflammatory responses.

In an attempt to better understand the role of IL-25 in inflammatory bowel disease (IBD), we have conducted preliminary experiments and evaluated the expression of IL-25 in colonic biopsies taken from patients with CD, patients with UC, and normal controls. Surprisingly, a marked down-regulation of IL-25 was seen in tissues from patients with IBD in comparison to controls. Analysis of IL-25 receptor (IL-25R) expression revealed that blood and intestinal CD14+ cells isolated from IBD patients express high levels of IL-25R, and are able to respond to IL-25 by down-regulating the production of several inflammatory molecules that are believed to play a major role in the pathogenesis of IBD. Based upon these data, we generated the hypothesis that a defective IL-25-mediated down-regulation of cytokine response can contribute to amplify the pathologic inflammation in IBD. Therefore, in this project, we will examine the role of IL-25 in the control of gut inflammation. To this end, we first plan to examine whether the reduced synthesis of IL-25 is a specific hallmark of IBD and which factors/mechanisms account for such a defect. Second, we will dissect the molecular mechanisms underlying the IL-25-mediated negative regulation of CD14+ cells-derived cytokines. Finally, we plan to confirm our preliminary data showing that IL-25 is also down-regulated in the colons of mice with experimental colitis, and examine whether administration of exogenous IL-25 to mice is useful to prevent and/or cure the mucosal inflammation.

Results from the proposed experiments will help clarify the role of IL-25 in the maintenance of gut immune homeostasis, and ascertain whether enhancing IL-25 activity is useful to attenuate the ongoing gut inflammation, thereby bringing important rewards in therapy of patients with IBD.