Abstract
Type 17 immune responses, typified by the production of the cytokines IL-17A and IL-17F, have been implicated in the development of type 1 diabetes in animal models and human patients, however the underlying pathogenic mechanisms have not been clearly elucidated. While previous studies show that IL-17A enhances inflammatory gene expression and cell death in mouse β-cells and human islets, the function of IL-17F in pancreatic β-cells is completely untested to date. Here we show that IL-17F exhibits potent pathogenic effects in mouse β-cell lines and islets. IL-17F signals via the IL-17RA and -RC subunits in β-cells and in combination with other inflammatory cytokines induces expression of chemokine transcripts, suppresses the expression of β-cell identity genes and impairs glucose stimulated insulin secretion. Further IL-17F induces cell death in primary mouse islets. This occurs via Jnk, p38 and NF-κB dependent induction of Nos2 and is completely ablated in the presence of an inducible nitric oxide synthase (iNOS) inhibitor. Together these data indicate that IL-17F possesses similar pathogenic activities to IL-17A in mouse β-cell lines and islets and is likely to be a type 17 associated pathogenic factor in type 1 diabetes.
Highlights
Type 17 immune responses, typified by the production of the cytokines IL-17A and IL-17F, have been implicated in the development of type 1 diabetes in animal models and human patients, the underlying pathogenic mechanisms have not been clearly elucidated
The sparse evidence to date indicates that IL-17F expression is increased in parallel with IL-17A in the pancreas of non-obese diabetic (NOD) mice at diabetes o nset[17], RORγt/RORα inverse agonists suppress IL-17F production in NOD m ice[21] and circulating IL-17F levels were increased in newly diagnosed type 1 diabetic patients[29]
These data suggest that IL-17F may have pathogenic functions in the context of type 1 diabetes that are yet to be defined
Summary
Type 17 immune responses, typified by the production of the cytokines IL-17A and IL-17F, have been implicated in the development of type 1 diabetes in animal models and human patients, the underlying pathogenic mechanisms have not been clearly elucidated. The sparse evidence to date indicates that IL-17F expression is increased in parallel with IL-17A in the pancreas of NOD mice at diabetes o nset[17], RORγt/RORα inverse agonists suppress IL-17F production in NOD m ice[21] and circulating IL-17F levels were increased in newly diagnosed type 1 diabetic patients[29]. These data suggest that IL-17F may have pathogenic functions in the context of type 1 diabetes that are yet to be defined. Our aim was to determine whether IL-17F exerts pathogenic activities in mouse pancreatic β-cells and islets
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
