S1712 CD14 Is a Protective Factor in Experimental IBD

Iron overload of Mode-K cells also induced HIF-1a expression, c-Jun phosphorylation and caspase-3 cleavage, suggesting that iron modulates ER and oxidative stress responses towards pro-apoptotic mechanisms in IEC. Conclusion. These studies clearly demonstrated that low dietary iron inhibits the development of chronic experimental ileitis in TNFDARE/WT mice associated with the attenuation of ER and oxidative stress responses in primary IEC. Mechanistically, iron triggered ER stress responses through post-transcriptional mechanisms targeting pro-apoptotic pathways in the epithelium.

S1713

Improper development and/or maintenance of intestinal immunity can lead to propensity for infectious disease or predispose to inflammatory bowel disease. Though the cellular components of the immune machinery of the intestine have been extensively investigated, few studies have focused directly on the signaling mechanisms by which intestinal epithelial cells impact the development and maintenance of immune cell populations of the lamina propria. We recently identified the Hedgehog (Hh) signaling pathway as a crucial regulator of intestinal immunity. Intestinal epithelial cells express both Sonic (Shh) and Indian (Ihh) during development and in adult life. All Hedgehog signaling is paracrine in the intestine; Hedgehog signals have been shown to impact the development and maintenance of several mesenchymal cell types. To identify specific Hedgehog target genes, we performed a microarray on intestinal mesenchyme treated with Shh, Ihh or vehicle. Gene Ontology profiling of the probe sets that exhibited significant change with Hh treatment indicated that over 60% of altered genes were linked to inflammatory pathways. We therefore investigated whether inflammatory cells of the intestinal lamina propria can respond to Hh signals. Using Gli1+/ LacZ reporter animals, which express LacZ in all cells responding to Hh signaling, we examined the response of various immune cell types in the intestine during development, homeostasis, and inflammation (after challenge with 3% DSS). These studies show that cells of both the myeloid and lymphoid lineages respond to Hh signals during intestinal homeostasis and inflammation. We also initiated studies to measure the intestinal response to inflammatory challenge in mouse models with alterations in Hh pathway components. We found that mice lacking one allele of Gli1 exhibit a robust inflammatory response to DSS treatment. After 6 days of 3% DSS treatment, 4/9 Gli1 heterozygotes died, compared to 0/ 14 WT littermates (p