Saturated fatty acids promote allergic (Th2) cytokine responses by activation of unfolded protein response (UPR) and ER stress

Endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) are stimulated by saturated, but not unsaturated fatty acids. We previously showed that saturated medium chain triglycerides (MCT) promote food allergy induction and increase epithelial cell expression of 3 pro-Th2 cytokines, TSLP, IL-25 and IL-33, which stimulate a Th2 cytokine response. These observations led us to hypothesize that the high concentrations of saturated triglycerides in two common food allergens, cow’s milk and chicken eggs, promote food allergy by inducing an epithelial cell UPR response, which in turn, causes these cells to express pro-Th2 cytokines. Indeed, studies with transformed human intestinal epithelial CACO2 cells demonstrated that MCT, egg yolk plasma (the liquid, triglyceride fraction of eggs) and cow’s milk cream each increase expression of the UPR-associated PERK, BiP, CHOP, XBP1 and/or XBP1s genes after 6 hours, followed by increased expression of all 3 pro-Th2 cytokine genes after 24 hours. Each of these stimuli, but not but not protein-rich, lipid-poor egg white, also increase epithelial permeability. Further, the increases in pro-Th2 cytokine expression are blocked by each of 3 UPR inhibitors: metformin, 4PBA and TUCDA, and the egg yolk plasma-induced increase in epithelial permeability is blocked by the only UPR inhibitor tested (metformin). Additionally, monoclonal antibodies (mAbs) to IL-25, IL-33 and TSLP each individually block the induction of egg white food allergy by a combination of egg white and MCTs, and a combination of these mAbs strongly suppress established egg white food allergy. These observations support our hypothesis and provide an explanation for the strong allergenicity of cow’s milk and chicken eggs.