Our long term objective is to determine the role of growth factors in the pathogenesis of inflammatory bowel disease and its complications. This proposal will study the expression of insulin-like growth factor I (IGF-I) in the peptidoglycan-polysaccharide (PG-PS) induced animal model of inflammatory bowel disease (IBD). Peptidoglycan-polysaccharide complexes are the primary structural cell wall component of nearly all bacterial species including normal intestinal flora. Injection of PG-PS complexes into the intestinal wall induces a chronic granulomatous enterocolitis with histological, systemic and immune manifestations similar to Crohn's disease. PG-PS activates nearly every arm of the immune response including the cytokines. Emerging evidence supports a role for interaction between the cytokines and mitogenic growth factors including IGF-i. Studies in other systems suggest that IGF-I may be important in inflammation, tissue remodeling, and fibrosis. Tissue remodeling processes probably underlie the spontaneous remission and reaction which is a unique feature of this model. In addition, prominent fibrosis present during the chronic phase of enterocolitis makes this model of IBD uniquely relevant to our study of IGF-I in IBD. Preliminary data from our laboratory show increased expression of IGF-I mRNA in the chronic phase of IGF-I induced enterocolitis. In situ hybridization studies have localized expression of IGF-I mRNA to cells surrounding granulomas in inflammatory nodules present in the chronic phase of PG-PS induced inflammation. This proposal will study expression of key elements of the IGF-I system in tissue from PG-PS injected and control animals in different phases of PG-PS induced inflammation. We will study the expression of IGF-I, IGF-II, and the IGF-I type I receptor which mediates the actions of IGF-I and IGF-II. IGF-I binding proteins which modulate IGF-I's endocrine and paracrine actions will also be studied. RNase protection assay will be used to measure IGF mRNAs in RNA extracted from intestinal tissues. Cellular localization of IGF-I and its receptor by in situ hybridization histochemistry and receptor autoradiography during different phases of inflammation will provide insight into potential paracrine interactions.
In specific aim 3, we will determine if infusion of IL-1 receptor antagonist which abrogates the chronic phase of PG-PS induced inflammation effects local expression of IGF-I. this is based on in vitro evidence suggesting that the cytokine, IL-1, mediates up-regulation of IGF-I mRNA in macrophages. We will also infuse an IGF-I monoclonal antibody to attempt to immunoneutralize local IGF-I and determine the effect on the chronic PG- PS induced inflammatory response. This project will study the role of IGF- I in the genesis of inflammation and fibrosis in inflammatory bowel disease. These studies will also provide insight into potential interactions between inflammatory cytokines and growth factors.
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