IL-17F induces inflammation, dysfunction and cell death in mouse islets

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.

Production of rAAV by plasmid transfection induces antiviral and inflammatory responses in suspension HEK293 cells

“…IL-17F, a pro-inflammatory cytokine that activates expression of other chemokines, was induced between the 24 and 36 h time points. 24 These DEGs identified in gene ontologies related to antiviral response suggest an active response to pathogen-associated stimuli in transfected HEK293.

Figure 3 Overview of transcriptional response to transfection and rAAV production (A) Number of up- and down-regulated DEGs with at a least 2-fold relative to pre-transfection (0 h) baseline.

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Contribution of Interleukin-17A to Retinal Degenerative Diseases

“…Studies have shown that IL-17F is more highly expressed in psoriasis and spondyloarthritis than IL-17A ( 46 ). It was demonstrated that IL-17F had similar pathogenic effects as IL-17A in β-cell lines and pancreatic islets in type I diabetic mouse models ( 47 ). In addition, IL-17F may also be involved in systemic sclerosis fibrosis and vascular disease ( 48 ).…”