Both GSH and redoxins are major factors with critical redox functions in RPE cells

transcription factor that is constitutively active in the intestinal mucosa of patients with untreated CD and is considered central to intestinal inflammation. Finally, it has been hypothesized that tTG-mediated downregulation of the PPARc signaling pathway in cells treated with p3143 may contribute to NF-kB activation and therefore plays a pivotal role in CD-associated inflammation. In line with this scenario, we observed that prolonged treatment of Caco-2 cells with p3143, but not with p5768, increased tTG mRNA and protein expression in Caco-2 cells. This finding supports the hypothesis that p3143 could induce tTGmediated pro-inflammatory modifications in cells. A large body of evidence suggests that Ca2+ is an important regulator of cell fate. An abrupt increase of intracellular Ca2+ is Ca2+ Mobilization Induced by Gliadin found in ischemia-reperfusion injury, receptor over-stimulation and oxidative stress. Depletion of Ca2+ from the ER, which is the most important intracellular store of Ca2+, can cause protein misfolding and ER-stress. ER-stress triggers a series of signaling and transcriptional events known as the unfolded protein response. The unfolded protein response attempts to restore homeostasis in the ER but, if unsuccessful, can trigger apoptosis in the stressed cells and local inflammation. Chaperone production is upregulated in response to increased misfolding, and the magnitude of the increase in chaperone levels, particularly GRP78, is widely used as a marker of ER-stress. Here we report that stimulation of Caco-2 cells with p3143 increases GRP78 mRNA expression by about nine-fold, and GRP78 protein levels by about 50% versus basal GRP78 levels in untreated cells. We also evaluated whether prolonged treatment with gliadin peptides could activate CHOP, a transcription factor that primarily mediates stress-linked apoptosis in cells with an irrecoverable level of ER-stress. We found a moderate but significant increase of CHOP expression in cells treated with p3143, but not with p5768. Interestingly, it was recently reported that ER-stress-induced CHOP can negatively modulate PPARc action, thus enhancing the pro-inflammatory response in human intestinal epithelial cells. ER-stress has been associated with an increasing number and wide variety of human diseases, namely, cancer, diabetes, developmental disorders, and neurodegenerative, infectious and inflammatory diseases. The concept that ER-stress, elicited by the gliadin peptide p3143, could be involved in CD is intriguing also because unresolved ER-stress leads to intestinal epithelial cell dysfunctions typical of the entity inflammatory bowel disease. In conclusion, given the direct links between ER-stress/unfolded protein response and local and systemic inflammation, we suggest that p3143, which is responsible for innate immunity in CD, could promote an ER-stress pathway by inducing rapid Ca2+ mobilization from the ER, and so amplify a local inflammatory response. Moreover, by mobilizing Ca2+ from intracellular stores, both p3143 and p5768 could induce tTGmediated modifications of several key regulators of the inflammatory response. Finally, intracellular tTG activation could allow deamidation of immunogenic gliadin peptides and the formation of gliadin-tTG complexes inside enterocytes and other MK886 specialized antigen-presenting cells, such as duodenal dendritic cells and macrophages, which contain large amounts of tTG. An essential physiologic function of the intestine