Aims/hypothesis: Cytotoxic T cells and macrophages contribute to beta cell destruction in type 1 diabetes at least in part through the production of cytokines such as IL-1β, IFN-γ and TNF-α. We have recently shown the IL-17 pathway to be activated in circulating T cells and pancreatic islets of type 1 diabetes patients. Here, we studied whether IL-17A upregulates the production of chemokines by human pancreatic islets, thus contributing to the build-up of insulitis. Methods: Human islets (from 18 donors), INS-1E cells and islets from wild-type and Stat1 knockout mice were studied. Dispersed islet cells were left untreated, or were treated with IL-17A alone or together with IL-1β+IFN-γ or TNF-α+IFN-γ. RNA interference was used to knock down signal transducer and activator of transcription 1 (STAT1). Chemokine expression was assessed by quantitative RT-PCR, ELISA and histology. Cell viability was evaluated with nuclear dyes. Results: IL-17A augmented IL-1β+IFN-γ- and TNF-α+IFN-γ-induced chemokine mRNA and protein expression, and apoptosis in human islets. Beta cells were at least in part the source of chemokine production. Knockdown of STAT1 in human islets prevented cytokine- or IL-17A+cytokine-induced apoptosis and the expression of particular chemokines, e.g. chemokine (C-X-C motif) ligands 9 and 10. Similar observations were made in islets isolated from Stat1 knockout mice. Conclusions/interpretation: Our findings indicate that IL-17A exacerbates proinflammatory chemokine expression and secretion by human islets exposed to cytokines. This suggests that IL-17A contributes to the pathogenesis of type 1 diabetes by two mechanisms, namely the exacerbation of beta cell apoptosis and increased local production of chemokines, thus potentially aggravating insulitis. © 2013 Springer-Verlag Berlin Heidelberg.
|Autori:||Fabio A., Grieco; Fabrice, Moore; François, Vigneron; Izortze, Santin; Olatz, Villate; Marselli, Lorella; Dieter, Rondas; Hannelie, Korf; Lutgart, Overbergh; Francesco, Dotta; Marchetti, Piero; Chantal, Mathieu; Décio L., Eizirik|
|Titolo:||IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets|
|Anno del prodotto:||2013|
|Digital Object Identifier (DOI):||10.1007/s00125-013-3135-2|
|Appare nelle tipologie:||1.1 Articolo in rivista|