Abstract
Mice expressing IL-23 constitutively in the intestine or skin fail to grow and die prematurely. These phenotypes are associated with marked changes in the levels of circulating cytokines and changes in the transcriptome of the pancreas and intestine, in particular in the expression of genes involved in the processing of nutrients. Marked changes are observed in the expression of molecules involved in digestion of carbohydrate, protein, and fat, resulting in malabsorptive condition. Genetic ablation of IL-22, or one of the subunits of the IL-22R, in mice expressing IL-23, restores normal growth and increases the life span of the animals. Mechanistically IL-22 acts directly at the level of pancreatic acinar cells to decrease expression of the pancreas associated transcription factor 1a (Ptf1a), an important transcription factor controlling acinar cell identity and expression of pancreatic enzymes. The results indicate that dysregulated expression of IL-23 and IL-22 have severe consequences in newborns and reveal an unsuspected role for IL-22 in the regulation of pancreatic enzyme regulation and food absorption.