IL-4 and IL-13 act on immune and epithelial cells to promote gastric metaplasia during autoimmune gastritis

Abstract

Abstract Chronic inflammation in the stomach can lead to peptic ulcers and is the highest independent risk factor for developing gastric cancer. Autoimmune gastritis (AIG) and infection with Helicobacter pylori are the two major causes of chronic gastritis. Cytokines released during chronic inflammation likely regulate the degree of tissue damage and the emergence of metaplasia, a precancerous condition believed to be the origin of gastric cancer. We recently discovered that mice with AIG that lack a receptor for IL-4/IL-13 (Il4ra−/−) developed mild gastritis but failed to develop gastric metaplasia. The objective of this study was to determine how IL-4 and/or IL-13 regulate disease development and severity. Immune assays revealed that autoantibody titers were high in control mice with AIG yet were nearly absent in Il4ra−/− mice with AIG. Epithelial cell assays revealed that both IL-4 and IL-13 also act on the gastric epithelium to promote growth and induce transcriptional changes associated with metaplasia. Finally, neutralizing antibodies to IL-4 and IL-13 were effective at ameliorating disease and preventing gastric metaplasia in mice with AIG. Together these data demonstrate that IL-4 and IL-13 play critical and complex roles in exacerbating gastric disease severity and metaplasia development by increasing production of tissue-damaging autoantibodies and inducing gastric metaplasia. These novel findings identify IL-4 and IL-13 as potential therapeutic targets for treatment of diseases induced by chronic gastritis.