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IFN-? induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells.

ABSTRACT: AIMS/HYPOTHESIS:IFN-?, a cytokine expressed in human islets from individuals affected by type 1 diabetes, plays a key role in the pathogenesis of diabetes by upregulating inflammation, endoplasmic reticulum (ER) stress and MHC class I overexpression, three hallmarks of islet histology in early type 1 diabetes. We tested whether expression of these mediators of beta cell loss is reversible upon IFN-? withdrawal or IFN-? pathway inhibition. METHODS:IFN-?-induced MHC class I overexpression, ER stress and inflammation were evaluated by flow cytometry, immunofluorescence and real-time PCR in human EndoC-?H1 cells or human islets exposed to IFN-? with or without the presence of Janus kinase (JAK) inhibitors. Protein expression was evaluated by western blot. RESULTS:IFN-?-induced expression of inflammatory and ER stress markers returned to baseline after 24-48 h following cytokine removal. In contrast, MHC class I overexpression at the cell surface persisted for at least 7 days. Treatment with JAK inhibitors, when added with IFN-?, prevented MHC class I overexpression, but when added 24 h after IFN-? exposure these inhibitors failed to accelerate MHC class I return to baseline. CONCLUSIONS/INTERPRETATION:IFN-? mediates a long-lasting and preferential MHC class I overexpression in human beta cells, which is not affected by the subsequent addition of JAK inhibitors. These observations suggest that IFN-?-stimulated long-lasting MHC class I expression may amplify beta cell antigen presentation during the early phase of type 1 diabetes and that IFN-? inhibitors might need to be used at very early stages of the disease to be effective.

SUBMITTER: Coomans de Brachene A

PROVIDER: S-EPMC6241216 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells.

Coomans de Brachène Alexandra A Dos Santos Reinaldo S RS Marroqui Laura L Colli Maikel L ML Marselli Lorella L Mirmira Raghavendra G RG Marchetti Piero P Eizirik Decio L DL

Diabetologia 20180105 3

<h4>Aims/hypothesis</h4>IFN-α, a cytokine expressed in human islets from individuals affected by type 1 diabetes, plays a key role in the pathogenesis of diabetes by upregulating inflammation, endoplasmic reticulum (ER) stress and MHC class I overexpression, three hallmarks of islet histology in early type 1 diabetes. We tested whether expression of these mediators of beta cell loss is reversible upon IFN-α withdrawal or IFN-α pathway inhibition.<h4>Methods</h4>IFN-α-induced MHC class I overexpr ...[more]

PMID: 29305625

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Project description:?-aminobutyric acid (GABA) pathways play an important role in neuronal circuitry formation during early postnatal development. Our previous studies revealed an increased risk for adverse neurodevelopmental consequences in animals exposed to benzodiazepines, which enhance GABA inhibition via GABAA receptors. We reported that administration of the benzodiazepine clonazepam (CZP) during postnatal days 7-11 resulted in permanent behavioral alterations. However, the mechanisms underlying these changes are unknown. We hypothesized that early CZP exposure modifies development of glutamatergic receptors and their composition due to the tight developmental link between GABAergic functions and maturation of glutamatergic signaling. These changes may alter excitatory synapses, as well as neuronal connectivity and function of the neural network. We used quantitative real-time PCR and quantitative autoradiography to examine changes in NMDA and AMPA receptor composition and binding in response to CZP (1 mg/kg/day) administration for five consecutive days, beginning on P7. Brains were collected 48 h, 1 week, or 60 days after treatment cessation, and mRNA subunit expression was assessed in the hippocampus and sensorimotor cortex. A separate group of animals was used to determine binding to NMDA in different brain regions. Patterns of CZP-induced alterations in subunit mRNA expression were dependent on brain structure, interval after CZP cessation, and receptor subunit type. In the hippocampus, upregulation of GluN1, GluN3, and GluR2 subunit mRNA was observed at the 48-h interval, and GluN2A and GluR1 mRNA expression levels were higher 1 week after CZP cessation compared to controls, while GluN2B was downregulated. CZP exposure increased GluN3 and GluR2 subunit mRNA expression levels in the sensorimotor cortex 48 h after treatment cessation. GluA3 was higher 1 week after the CZP exposure, and GluN2A and GluA4 mRNA were significantly upregulated 2 months later. Expression of other subunits was not significantly different from that of the controls. NMDA receptor binding increased 1 week after the end of exposure in most hippocampal and cortical areas, including the sensorimotor cortex at the 48-h interval. CZP exposure decreased NMDA receptor binding in most evaluated hippocampal and cortical areas 2 months after the end of administration. Overall, early CZP exposure likely results in long-term glutamatergic receptor modulation that may affect synaptic development and function, potentially causing behavioral impairment.

Dataset Information

IFN-? induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells.

Publications

IFN-α induces a preferential long-lasting expression of MHC class I in human pancreatic beta cells.

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