5 General discussion
5.7 Concluding remarks
We successfully showed that cIAP1 adopts a key role in the TNF-mediated cell death induction of IECs, which could be contributing to various pathophysiological conditions of the intestine, such as CD, UC and GvHD. Moreover, our data and conclusions are potentially of high relevance for the stratification of IBD patients , for instance by analyzing the intestinal protein levels of cIAP1 in IBD patients, and correlating it to their disease stage, resp. their response to anti-TNF antibody treatment. This study provides evidence that a reduced activity of cIAP1 in IECs leads to atypical TNF susceptibility, which is independent of any co-stimulus applied, such as transcriptional blockage. An induced absence of cIAP1 at the TNFR1 site, for instance after IAPs degradation or their competitive recruitment to Fn14, also led to a strongly increased TNF-mediated cell death response in IECs. Our results demonstrate the crucial role of TNF in intestinal cells, and cIAP1 as the key factor of its pro-apoptotic action, by using an array of model systems, like several cellular models and an in vivo model. Additionally, we developed an easy-to-handle intestinal organoid-based cell viability assay, which allows objective mid- to high-throughput analysis of specimens. We showed the potential of this new method not only by using it for our current research projects, but also to demonstrate its pre-clinical drug screening capacity. Examples for possible applications of this method in the future are the determination of side-effects of chemotherapeutic drugs, or the identification of the role of particular proteins in cell death pathways by parallel usage of wild type- and knockout mouse-derived organoids.
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