RGD Reference Report - Peripheral and Islet Interleukin-17 Pathway Activation Characterizes Human Autoimmune Diabetes and Promotes Cytokine-Mediated {beta}-Cell Death. - Rat Genome Database

RGD Reference Report - Peripheral and Islet Interleukin-17 Pathway Activation Characterizes Human Autoimmune Diabetes and Promotes Cytokine-Mediated {beta}-Cell Death. - Rat Genome Database

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Peripheral and Islet Interleukin-17 Pathway Activation Characterizes Human Autoimmune Diabetes and Promotes Cytokine-Mediated {beta}-Cell Death.
Authors:	Arif, S Moore, F Marks, K Bouckenooghe, T Dayan, CM Planas, R Vives-Pi, M Powrie, J Tree, T Marchetti, P Huang, GC Gurzov, EN Pujol-Borrell, R Eizirik, DL Peakman, M
Citation:	Arif S, etal., Diabetes. 2011 Aug;60(8):2112-9. Epub 2011 Jun 9.
RGD ID:	5144218
Pubmed:	PMID:21659501 (View Abstract at PubMed)
PMCID:	PMC3142078 (View Article at PubMed Central)
DOI:	DOI:10.2337/db10-1643 (Journal Full-text)
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 beta-cell autoantigens, IL-17A gene expression in islets, and the potential functional consequences of IL-17 release for beta-cells. RESEARCH DESIGN AND METHODS Peripheral blood CD4 T-cell responses to beta-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 beta-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 beta-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-1beta/interferon (IFN)-gamma-induced and tumor necrosis factor (TNF)-alpha/IFN-gamma-induced apoptosis in human islets, rat beta-cells, and INS-1E cells, in association with significant upregulation of beta-cell IL17RA expression via activation of the transcription factors STAT1 and nuclear factor (NF)-kappaB. CONCLUSIONS Circulating IL-17(+) beta-cell-specific autoreactive CD4 T-cells are a feature of type 1 diabetes diagnosis. We disclose a novel pathway to beta-cell death involving IL-17 and STAT1 and NF-kappaB, rendering this cytokine a novel disease biomarker and potential therapeutic target.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Il17ra	Rat	cellular response to cytokine stimulus		IDA		IL-1β and /IFN-γ	RGD

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Genes (Rattus norvegicus)

Il17ra (interleukin 17 receptor A)

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