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

应激反应基因即刻早期反应3(IER3)在炎症和肿瘤发生中具有双重作用。在上皮细胞和上皮细胞来源的肿瘤细胞中，IER3具有促凋亡活性，而在免疫细胞和血液肿瘤细胞中则具有抑制凋亡的作用。这种双重作用模式是由于对控制细胞生存的基本途径的不同调控，如核因子-kappaB、ERK-和PI3K/Akt。最近对结构性Ier3基因敲除小鼠的研究证实了IER3在炎症性疾病中的这种不同作用，例如在葡聚糖硫酸钠(DSS)结肠炎和结肠炎相关癌变(CAC)中。在某种程度上，IER3在组织巨噬细胞和T淋巴细胞中的一种尚未明确的功能可能是迄今为止使用的小鼠模型中不同效果的原因。针对IER3在肠道炎症和癌变病理生理学中的高度复杂性，在肠细胞、髓系细胞(特别是巨噬细胞)和CD4+T细胞(特别是Th17-细胞)中表达IER3的条件性基因敲除小鼠将分别用于建立慢性结肠炎和CAC的DSS和AOM/DSS体内模型。通过这些实验，我们可以详细了解IER3在肠上皮炎症和上皮应激适应中的生理作用。因此，我们的研究将大大提高对IER3作为免疫调节剂和肿瘤抑制因子的功能的理解。

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.