Lay Summary

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

Inflammatory bowel disease (IBD) is the general term including Crohn’s disease (CD) and ulcerative colitis (UC), two chronic inflammatory disorders of the intestine, which have different morphological, immunological and clinical characteristics. The etiology of IBD is still unknown, but in recent years, it has become evident that both CD and UC are caused by excessive intestinal immune reactivity that is directed against normal constituents of the luminal bacterial flora. Evidence also suggests that an altered balance between inflammatory and anti-inflammatory molecules (e.g., cytokines) may contribute to amplify and sustain the tissue-damaging immune response. These advances led to the development of novel therapeutic agents that are currently being studied for their capacity to specifically target the inflammatory pathways occurring in IBD patients.

We have preliminarily shown that the production of a newly described cytokine, termed interleukin (IL)-25, is markedly down-regulated in the inflamed intestine of patients with CD and patients with UC as compared with controls. Moreover, our preliminary data show that the receptor for IL-25 (IL-25R) is highly expressed on blood and intestinal CD14+ cells that are known to produce several inflammatory cytokines following stimulation with bacterial products/components. Notably, exposure of CD14+ cells to IL-25 resulted in a significant inhibition of bacterial stimuli-driven inflammatory cytokine synthesis. Therefore, we have hypothesized that a defective IL-25-mediated down-regulation of cytokine response can contribute to the pathologic inflammation in IBD. The aim of this project is to examine the role of IL-25 in the control of gut inflammation. For this purpose, we first plan to examine whether the reduced production 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 IBD-like 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 establish whether enhancing IL-25 activity helps attenuate the ongoing intestinal inflammation.