Lipopolysaccharide-induced cytokine signaling activates a temporal innate defense program and represses pancreatic β-cell identity.

Cytokine exposure has been promoted as one cause for the loss of β-cell mass during the development of type 1 diabetes. While in vitro studies have shown that cytokines inhibit insulin secretion and induce islet degeneration, interventions targeting these soluble mediators have had limited success in preventing disease development in rodents and humans. To understand the in vivo actions of cytokines in the endocrine pancreas, we explored the transcriptional responses of islets to endogenously produced cytokines following immune stimulation with the bacterial pathogen-associated molecular pattern lipopolysaccharide. We found that endogenous cytokine production in response to lipopolysaccharide administration stimulates the rapid, time-dependent expression of antiviral, antibacterial, and antioxidant genes and represses the expression of β-cell identity factors in islets. Changes in gene expression are associated with similar changes in protein expression and the actions are transient, with a return to control levels of gene expression 24 h post lipopolysaccharide administration. In contrast to a role in diabetes development, our findings support a physiologically relevant and dynamic immune-endocrine communication axis that is characterized by a cytokine-initiated cell-intrinsic defense response in the endocrine pancreas that has evolved to enhance the fitness of these essential cells during host infection.