Final Progress Report
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
Lay summary:
Interleukin-1 is a potent pro-inflammatory cytokine. While IL-1 has previously been linked to IBD the potential involvement of its receptor and intracellular signaling pathways have not previously been examined. Furthermore, recently several novel cytokines, related to IL-1, were discovered. We hypothesized that imbalances in the IL-1 system could cause or contribute to IBD. Our analyses of a subset of the initially proposed system genes revealed that the majority of IBD patients have relative elevated expression of one or more genes suggesting that they could benefit from IL-1 neutralizing therapy. One such agent, soluble IL-1 receptor accessory protein, was further evaluated as a potential novel therapeutic modality. Recombinant protein was expressed and functional activity tested; however, this was associated with several technical limitations and difficulties which make this agent an unlikely viable candidate for further commercial development.
A partially independent goal was to initiate studies of the function(s) of a series of novel proteins related to IL-1. Based on preliminary published studies we anticipated that these proteins would be expressed in cells derived from the small intestine and colon. Surprisingly we found expression of these genes to be absent or very low in these cells. We further speculated that in humans expression could be induced by the microbiota in the digestive tract. We therefore tested whether a panel of agents derived from different types of bacteria and viruses could increase expression of the genes in question. Gene expression was surprisingly and disappointingly found to be unaffected. We also examined expression of these genes in a mouse model of IBD. Again we were disappointed in that the expression levels were too inconsistent to draw any conclusions.
In summary the study supports the hypothesis that the majority of IBD patients could benefit from therapies aimed at neutralizing/blocking the action of IL-1 and/or related cytokines. The sIL-1RAcP is not expected to be a suitable novel therapeutic and functions of novel cytokines related to IL-1 remain unknown.