Cell type specific role of the stress response gene Immediate Early Response-3 (IER3) in intestinal inflammationand carcinogenesis

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The stress response gene Immediate Early Response-3 (IER3) has a dual role in inflammation and tumorigenesis. In epithelial and epithelial cell-derived tumor cells, IER3 exerts a proapoptotic activity whereas it inhibits apoptosis in immune cells and haematologic tumor cells. This dual mode of action is due to a differential regulation of essential pathways governing cell survival, such as NF-kappaB, ERK- and PI3K/Akt. Recent studies with constitutive ier3 knock out mice confirmed this divergent role of IER3 in inflammatory diseases, e.g. in Dextran-Sodium-Sulfate (DSS) colitis and colitis associated carcinogenesis (CAC). To someextent, a yet undefined function of IER3 in tissue macrophages and T-lymphocytes may be responsible for the discrepant effects in the mouse models used so far. Addressing the high complexicity of the IER3 effects in the pathophysiology of gut inflammation and carcinogenesis, conditional knock-out mice exhibiting an ablated ier3 expression in enterocytes, myeloid cells (in particular macrophages) and CD4+ T-cells (in particular Th17-cells) will be used for the established DSS and azoxymethan (AOM)/DSS in vivo models for chronic colitis and CAC, respectively. These experiments allow detailed insights into the physiological role of IER3 in the epithelial as well as in the leucocytic compartment with respect to intestinal inflammation and epithelial stress adapation. Thereby, our study will substantially improve the understanding of the functions of IER3 as immune modulator and tumorsuppressor.