IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

Abstract

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.

Th1/Th17 Plasticity Is a Marker of Advanced β Cell Autoimmunity and Impaired Glucose Tolerance in Humans

“…In experimental autoimmune encephalomyelitis, most pathogenic IFN-g-producing cells were derived from Th17 cells in chronic inflammatory settings (26). In the present study, we observed a remarkable increase in the IFN-g/IL-17 ratio in highly purified Th17 cells from children with advanced b cell autoimmunity and clinical type 1 diabetes, suggesting a similar shift from the Th17 phenotype toward the Th1/ (6,8,11).…”

“…IL-17 increased b cell apoptosis and upregulated the expression of stress response genes and proinflammatory chemokines in b cells (6,8,11). Accordingly, the upregulation of Th17 immunity could contribute to the destruction of b cells and the development of type 1 diabetes.…”

A Combined “Omics” Approach Identifies N-Myc Interactor as a Novel Cytokine-induced Regulator of IRE1α Protein and c-Jun N-terminal Kinase in Pancreatic Beta Cells

“…Under our experimental conditions, however, activation of STAT-regulated pathways cannot explain the phenotype induced by NMI KD. Thus, we observed that NMI KD increases cytokine-induced apoptosis in INS-1E and human islet cells, whereas STAT1 KD protects beta cells against cytokine-induced apoptosis (34,50,69). Furthermore, STAT1 silencing decreases NO production in cytokinetreated beta cells (50), whereas NMI KD does not change it (Fig.…”

“…The same medium, but with 2% FBS, was used during the cytokine treatment as described (34). The human embryonic kidney cells HEK293T were cultured in DMEM containing 25 mM glucose, 5% FBS, 100 units/ml penicillin, 100 g/ml streptomycin, and sodium pyruvate 100ϫ (Invitrogen).…”

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

“…Insulitis occurs in the context of a "dialog" between invading immune cells and the target pancreatic b-cells (1), which includes upregulation of islet human leukocyte antigen (HLA) class I expression in b-cells (2) and production of chemokines such as CXCL10 by the islet cells (3)(4)(5).…”