טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentShirly Moshe-Belizowsky
SubjectIron Regulatory Protein 1 is a Key Player of the
Inflammatory Process in Inflammatory Bowel Disease
DepartmentDepartment of Biotechnology and Food Engineering
Supervisor Dr. Meyron Holtz Esther


Abstract

Iron is an essential nutrient involved in many central cellular processes, such as electron transport in the respiratory chain and DNA synthesis. Moreover, iron is important for immune-surveillance, including: lymphocytes proliferation and activation, T cells and monocytes differentiation, and modulation of cytokine activities.  On the contrary, excess iron is potentially toxic as it can participate in Fenton reactions leading to the formation of reactive oxygen species (ROS), which can damage lipid membranes, proteins and nucleic acids. Paradoxically, both iron deficiency and iron overload have previously been reported to enhance inflammation, suggesting that a fine tuning of intestinal iron levels is necessary to avoid chronic inflammation. Altered iron homeostasis was previously found in various human disorders, including Inflammatory Bowel Diseases (IBD), in which elevated iron levels were determined in the inflamed intestinal tissues. Patients with IBD also commonly suffer from a state of anemia. The broad effects of inflammation on systemic iron homeostasis have been studied extensively, but not much is known yet on the mutual effects of the inflammation on local iron homeostasis and of the disrupted local cellular iron homeostasis on inflammation in the inflamed tissue. To evaluate these effects iron homeostasis was examined in depth in two main IBD models: a cellular model, in which inflammation was induced in the intestinal epithelial cells, Caco-2, by a NO-donor and the TNFΔARE/ mouse model.  

We found that while in normal physiological conditions IRP2 is the dominant regulator of iron metabolism and IRP1 is mainly active as a cytosolic aconitase, during the intestinal inflammation IRP1 was constitutively active in both the inflamed Caco-2 cells and in the inflamed intestinal tissue of the TNFΔARE/  mice. The unregulated IRP1 activation resulted in significant alterations in the expression levels of the proteins involved in maintaining iron homeostasis and in profound altered iron distribution in the inflamed tissue. While iron was accumulated in the immune cells infiltrating the tissue, the iron levels in the intestinal epithelial cells were decreased, suggesting that the epithelial cells suffer from relative iron deficiency.

In addition, we further emphasized IRP1 destructive role in the inflammation process and in the altered iron homeostasis by showing that IRP1 deletion in the IBD mouse model completely abolished the intestinal histological inflammation phenotypes, reduced the local TNF-α expression levels, and reduced the local iron levels. Therefore, we conclude with the suggestion that IRP1 specific inhibitors could be used as a possible therapy for IBD.