Iron-induced oxidative stress up-regulates calreticulin levels in intestinal epithelial (Caco-2) cells

Calreticulin, a molecular chaperone involved in the folding of endoplasmic reticulum synthesized proteins, is also a shock protein induced by heat, fo od deprivation, and chemical stress. Mobilferrin, a cytosolic isoform of ca lreticulin, has been proposed to be an iron carrier for iron recently incom ing into intestinal cells. To test the hypothesis that iron could affect ca lreticulin expression, we investigated the possible associations of calreti culin with iron metabolism. To that end, using Caco-2 cells as a model of i ntestinal epithelium, the mass and mRNA levels of calreticulin were evaluat ed as a function of the iron concentration in the culture media. Increasing the iron content in the culture from 1 to 20 muM produced an increase in c alreticulin mRNA and a two-fold increase in calreticulin. Increasing iron a lso induced oxidative damage to proteins, as assessed by the formation of 4 -hydroxy-2-nonenal adducts. Coculture of cells with the antioxidants querce tin, dimethyltiourea and N-acetyl cysteine abolished both the iron-induced oxidative damage and the iron-induced increase in calreticulin. We postulat e that the iron-induced expression of calreticulin is part of the cellular response to oxidative stress generated by iron. (C) 2001 Wiley-Liss, Inc.