Lay Summary

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

The human body normally reacts to pathogen exposure with immune responses involving reorganization of the affected tissue and changes in gene expression (protein production). These responses are often referred to as inflammation and are aimed at preventing infection and if infection has occurred eliminating the pathogen. Crohn’s disease and ulcerative colitis involve inflammation, which for unknown reasons have become chronic and, therefore, cause damage to the digestive tract. The immune system functions, in part, through a delicate communication system between cells involving a group of proteins called cytokines. Cytokines are recognized by another group of proteins called receptors. This interaction triggers a cascade of events involving additional proteins inside the cells, which further leads to increased gene expression and production of proteins involved in the immune responses. Interleukin-1 is a classical cytokine, which is involved in initiating inflammation. Several novel proteins have recently been discovered that appear to be either cytokines or receptors related to IL-1 and its receptor. However, the functions of these novel proteins are largely unknown. We believe that they are involved in regulating inflammation in the digestive tract and that they may be involved in causing inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.

Mechanisms have evolved to ensure that the inflammatory response is only activated when needed. Such mechanisms may involve anti-inflammatory proteins, which directly bind cytokines or prevent the cytokines from binding to their receptors. Collectively this complex network of pro- and anti-inflammatory proteins is called the IL-1 system. We hypothesize that imbalances of 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 indicate novel approaches for designing new and improved treatments using either so-called biologics, which are administered through injections, or synthetic compounds that may be taken in tablet form. 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 having their treatment based on the specific problem in their immune system.