Regulation of immunosuppressive molecules in IBD

University Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION (provided by applicant): A single layer of intestinal epithelial cells (IEC) protects the host from the toxic luminal environment. These cells are in close proximity with lamina propria immune cells and likely communicate with each other by direct contact and/or secretion of soluble mediators. Interestingly, the mucosa of the distal ileum and colon is constantly exposed to a complex microbial flora, yet no pathological inflammation occurs in normal hosts. This suggests that IEC gene expression must be tightly regulated to avoid overreaction to ubiquitous luminal bacterial products, yet be able to transiently respond to environmental pathogens. Although the repertoire of proinflammatory molecules synthesized by IEC has been identified, little is known about how these cells regulate coordinated expression and suppression of these genes. In addition, the intracellular signaling pathways associated with IEC gene expression are still poorly understood. Finally, the kinetics and distribution of NF-kappaB-activated cells during the course of an intestinal inflammatory process is currently unclear, much less during treatment intervention. We have shown that the NF-kappaB pathway regulates expression of a number of proinflammatory cytokines and adhesion molecules in IEC. Interestingly, native IEC and most transformed colonic cell lines show a unique IkappaBa phosphorylation and degradation process that distinguishes these cells from other cell lineages. Our hypothesis is that normal lEC have a unique NF-kappaB signaling pathway which buffers their cellular responses to the aggressive luminal environment. This hypothesis will be tested by addressing the following SPECIFIC AIMS: 1) Dissect the unique IkappaB/NF-kappaB signal transduction in transformed and native IEC following stimulation with environmentally relevant cytokines and commensal bacteria and explore mechanisms of suppression of this pathway by TGFbeta 2) Determine the physiological role of NF-kappaB in acute and chronic intestinal inflammation and tissue repair by using kappaB-green fluorescence protein transgenic mice with experimental colitis in combination with selective inhibition of the NF-kappaB pathway. Our ultimate goal is to prevent the onset and relapse of inflammatory bowel diseases (IBD) by manipulating key regulatory signaling proteins involved in central inflammatory pathways.