Scientific Abstract

Proposal No. IBD-0192R
Principal Investigator:  Liselotte Jensen, Ph.D.
Applicant Organization:  University of Pennsylvania (Philadelphia, U.S.A.)
Project Title:  Interleukin-1 system in inflammatory bowel disease and implications for the development of novel therapies
Period of Award:  March 1, 2007 – February 28, 2010

Crohn’s disease and ulcerative colitis are inflammatory bowel diseases characterized by chronic inflammation of the digestive tract. Although the cause(s) of these diseases remain elusive it is known that cytokines play important roles in these pathologies. Cytokines mediate recruitment of leukocytes and alter cellular phenotype and expression profiles of epithelial cells and other cells residing in the digestive tract. Interleukin-1 (IL-1) is a pleiotropic cytokine and acts via a transmembrane receptor complex involving the IL-1 receptor type I (IL-1R1) and membrane bound IL-1 receptor accessory protein (mIL-1RAcP). Assembly of this trimeric membrane complex activates an elaborate intracellular signaling cascade involving multiple kinases and adapter proteins. Signaling leads to altered gene expression profiles, which facilitate inflammation. IL-18 is related to IL-1 and functions via receptor components resembling IL-1R1 and mIL-1RAcP; hence IL-18 activates largely the same intracellular signaling pathways as IL-1. Recent advances in the IL-1 field have identified series of proteins related to IL-1, IL-1R1 and mIL-1RAcP, including novel cytokines that utilize a novel receptor, IL-1R related protein-2, which is primarily expressed in epithelial tissues such as the digestive tract. The functions of many of these novel proteins are currently unknown; however, their tissue distribution and other preliminary studies suggest that they are of particular importance for maintaining homeostasis in the digestive tract. Their potential involvement in IBD has never been examined.

Excessive inflammatory responses may lead to tissue damage and/or chronic inflammation. Therefore, progression of signaling is tightly regulated through an intricate network of inflammation modulators. These anti-inflammatory mechanisms may involve extracellular cytokine neutralizing binding proteins, receptor antagonists and receptor decoys. Several intracellular mechanisms are also in play and may involve inhibition of kinase activities and protein-protein interactions. Collectively this complex network of pro- and anti-inflammatory proteins is called the IL-1 system. We hypothesize that imbalances of both extracellular and intracellular pro- and anti-inflammatory mechanisms of the IL-1 system may lead to inflammatory bowel conditions such as Crohn’s disease and ulcerative colitis. We will perform a comprehensive analysis of the expression of the IL-1 system in tissue specimens obtained from healthy individuals and patients with either Crohn’s disease or ulcerative colitis. This study may lead to new directions for research aimed at identifying the cause(s) of inflammatory bowel diseases. It may also identify novel molecular targets for new treatments using either recombinant proteins, neutralizing antibodies or small interfering molecules. We may find that different patients have distinct imbalances of pro- and anti-inflammatory proteins, yet have the same disease. This would suggest that patients could benefit from individualized therapeutic strategies targeting the specific immune imbalance.