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Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated ?-cell death.
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ABSTRACT: Objective
CD4 T-cells secreting interleukin (IL)-17 are implicated in several human autoimmune diseases, but their role in type 1 diabetes has not been defined. To address the relevance of such cells, we examined IL-17 secretion in response to ?-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for ?-cells.Research design and methods
Peripheral blood CD4 T-cell responses to ?-cell autoantigens (proinsulin, insulinoma-associated protein, and GAD65 peptides) were measured by IL-17 enzyme-linked immunospot assay in patients with new-onset type 1 diabetes (n = 50). mRNA expression of IL-17A and IFNG pathway genes was studied by qRT-PCR using islets obtained from subjects who died 5 days and 10 years after diagnosis of disease, respectively, and from matched control subjects. IL-17 effects on the function of human islets, rat ?-cells, and the rat insulinoma cell line INS-1E were examined.Results
A total of 27 patients (54%) showed IL-17 reactivity to one or more ?-cell peptides versus 3 of 30 (10%) control subjects (P = 0.0001). In a single case examined close to diagnosis, islet expression of IL17A, RORC, and IL22 was detected. It is noteworthy that we show that IL-17 mediates significant and reproducible enhancement of IL-1?/interferon (IFN)-?-induced and tumor necrosis factor (TNF)-?/IFN-?-induced apoptosis in human islets, rat ?-cells, and INS-1E cells, in association with significant upregulation of ?-cell IL17RA expression via activation of the transcription factors STAT1 and nuclear factor (NF)-?B.Conclusions
Circulating IL-17(+) ?-cell-specific autoreactive CD4 T-cells are a feature of type 1 diabetes diagnosis. We disclose a novel pathway to ?-cell death involving IL-17 and STAT1 and NF-?B, rendering this cytokine a novel disease biomarker and potential therapeutic target.
SUBMITTER: Arif S
PROVIDER: S-EPMC3142078 | biostudies-literature | 2011 Aug
REPOSITORIES: biostudies-literature
Publications
Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated β-cell death.
Diabetes 20110609 8
<h4>Objective</h4>CD4 T-cells secreting interleukin (IL)-17 are implicated in several human autoimmune diseases, but their role in type 1 diabetes has not been defined. To address the relevance of such cells, we examined IL-17 secretion in response to β-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for β-cells.<h4>Research design and methods</h4>Peripheral blood CD4 T-cell responses to β-cell autoantigens (proinsulin, insulinoma-a ...[more]