Protein folding in the endoplasmic reticulum (ER) is subject to stringent quality control. When protein secretion demand exceeds the protein folding capacity of the ER, the unfolded protein response (UPR) is triggered as a consequence of ER stress. Due to the secretory function of epithelial cells, UPR plays an important role in maintaining epithelial barrier function at mucosal sites. ER stress and activation of the UPR are natural mechanisms by which mucosal epithelial cells combat viral infections. The UPR plays an important role in regulating mucosal epithelium homeostasis and is regulated by the immune response during infection. Whilst it is well accepted that ER stress initiates inflammatory signalling via the UPR, the influence of local inflammatory factors on ER stress has received less attention. We have discovered that specific inflammatory cytokines (IL-24, being the most potent) initiate ER stress by inducing oxidative stress, whilst other counteracting cytokines (IL-22, being the most potent) suppress stress and facilitate ER protein folding. We show that cytokine regulation of cellular stress is common to multiple different epithelial cell types including intestinal and respiratory epithelial cells and pancreatic beta cells. Thus, immunity has evolved mechanisms centred on the IL-22/IL-24 family cytokines by which it can rapidly up- or downregulate ER protein biosynthesis at the most common sites of infection.