Cell-specific impact of IER3 on inflammation and carcinogenesis in the colon

Inflammatory bowel disease is a chronic inflammation disorder affecting mainly the colon and the small intestine. A common concomitant feature of this disease is the formation of colorectal cancer, causing worldwide about 38000 deaths per year. To date, the pathomechanisms underlying this disease are only partially known. Besides environmental factors and genetic alterations, an inadequate immune response to the host’s microbiome significantly contributes to the onset as well to the progression of the disease. Furthermore, macrophages have been identified as a cell type, highly involved in the pathophysiology of inflammatory bowel disease and colorectal carcinogenesis. The immediate early response gene Ier3, whose expression is highly up-regulated in patients suffering from inflammatory bowel disease, plays an important role in the cellular response to stress stimuli. Ier3 not only influences the regulation of apoptosis and proliferation but also affects several immunologic pathways, for instance by interacting with the NF-κB signaling cascade. In this project we analyzed the effects of a cell type specific depletion of Ier3 on the outcome of colitis and colitis associated carcinogenesis using an AOM/DSS mouse model. We were able to show, that a macrophage specific depletion of Ier3 significantly attenuates the severity of an AOM/DSS induced colitis as well as the formation of colorectal tumors. This protective effect was much less pronounced in an epithelial cell specific or genome wide depletion of Ier3. Furthermore, we observed a reduced responsiveness of Ier3 deficient macrophages to immunogenic stimuli like bacterial LPS, which manifests in a significantly decreased expression of the inducible nitric oxide synthase and a diminished release of reactive nitrogen species. As a result, these macrophages affect the integrity of the intestinal epithelial cell barrier to a much lesser extent when compared to activated Ier3 proficient macrophages. This relates to a differential effect on the transepithelial permeability caused by an altered expression and intracellular distribution of the cellular junction associated proteins E-cadherin and β-catenin as we could demonstrate in vivo and in vitro. In summary, our results reveal a novel mechanism how IER3 contributes to inflammatory bowel disease and colitis associated carcinogenesis.