Scientific Abstract

Proposal No.  IBD-0160
Principal Investigator:  Atsushi Mizoguchi, M.D., Ph.D.
Applicant Organization:  Massachusetts General Hospital (Boston, U.S.A.)
Project Title:  Therapeutic approach using interleukin-22 in experimental colitis
Period of Award:  November 1, 2005 – April 30, 2008

Normal intestinal homeostasis is constitutively maintained to prevent the development of inflammatory bowel disease (IBD) by a complicated cell network in which several cell subsets (including acquired and innate immune cells and epithelial cells) interact closely.  The effects of certain factors, such as signal transducer and activator of transcription (STAT) 3, differ depending upon the cell types involved.  For example, activation of STAT3 cascade induces pathogenic activity in acquired immune cells and, alternatively, induces regulatory activity in innate cells, such as epithelial cells and macrophages under intestinal inflammatory conditions.  Therefore, therapeutic approaches targeting a wide variety of cell types may not be effective therapeutically.

In our preliminary studies, we have found that expression of IL-22, an IL-10 family member, is induced in experimental colitis models as well as in human IBD patients.  Interestingly, the expression level of IL-22 in IBD patients was relatively low compared to that in experimental colitis.  However, the receptors for IL-22 were constitutively expressed on the epithelial cells and macrophages, but not other cell types in the colon of IBD patients.  Functionally, IL-22 suppresses experimental acute and chronic colitis.  In addition, several recent studies have indicated that IL-22 specifically activates STAT3 in innate, but not acquired, cells.  Therefore, we hypothesize that a strategy to enhance IL-22 expression contributes to the attenuation of IBD by specifically facilitating the STAT3-mediated activation of innate responses without activation of acquired immune responses.  In addition, neutralization of IL-6 has been shown to be beneficial in experimental IBD models and also Crohn’s disease patients by suppressing STAT3 activity in acquired immune cells.  Since this therapeutic strategy could concurrently downregulate STAT3 activation in regulatory innate cells, we also hypothesize that selective restoration of STAT3 activity in innate cells by enhanced IL-22 production would further promote the therapeutic effect of IL-6 neutralization in IBD patients.  We plan to test our hypotheses by examining IBD patients and also experimental colitis models.  This information will provide an important rationale to develop a novel and more effective therapeutic approach to improve the lives of patients with IBD.