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P046 Iron mobilisation into the intestinal epithelium prevents hypoxia-associated autophagy and reduces inflammation through the inhibition of NF-κB

S. Simmen1, J. Cosin-Roger1, H. Melhem1, N. Maliachovas1, M. Maane1, K. Baebler1, B. Weder1, C. Maeyashiki1, K. Spanaus1, M. Scharl1, C. de Vallière1, J. Zeitz1, S. R. Vavricka1, M. Hausmann1, G. Rogler1, P. A. Ruiz-Castro1

1University of Zurich / University Hospital Zurich, Gastroenterology and Hepatology, Zurich, Switzerland

Background

Environmental hypoxia influences the development of inflammatory bowel diseases. Adaptive responses to hypoxia are mediated through hypoxia-inducible factors, which are tightly regulated by oxygen- and iron-dependent hydroxylases. Regulation of uptake, storage and export of iron is mediated by signals reflecting oxygen and intracellular iron levels in enterocytes. Conversely, iron modulates responses to hypoxia. We sought to elucidate the effects of iron levels on hypoxia-associated responses in the intestinal epithelium.

Methods

Human subjects were exposed to hypoxia, and colonic biopsies and serum samples were collected. The human intestinal epithelial cells HT-29, Caco-2 and T84 were subjected to hypoxia in the presence of iron or the iron chelator deferoxamine. Changes in inflammatory gene expression and signalling were assessed by qPCR and western blot. Chromatin immunoprecipitation was performed using antibodies against NF-κB and primers for promoter binding regions of TNF and IL-1β

Results

Human subjects presented reduced levels of ferritin and iron in the intestinal epithelium following hypoxia. Hypoxia reduced iron deprivation-associated TNF and IL-1β expression in HT-29 cells through the induction of autophagy. Contrarily, hypoxia triggered TNF and IL-1β expression, and NF-κB activation in Caco-2 and T84 cells. In Caco-2 cells, iron blocked early and late-stage autophagy while reducing hypoxia-associated TNF and IL-1β expression, and the binding of NF-κB to the promoter of TNF and IL-1β.

Conclusion

Hypoxia-induced autophagy reduces inflammation in HT-29 cells. In Caco-2 cells, iron uptake is essential to prevent hypoxia-induced inflammatory processes. Iron mobilisation plays a crucial role in the maintenance of homeostasis in the hypoxic intestinal epithelium.