Interferon alpha impairs insulin production in human beta cells via endoplasmic reticulum stress.

ABSTRACT: Despite substantial advances in the research exploring the pathogenesis of Type 1 Diabetes (T1D), the pathophysiological mechanisms involved remain unknown. We hypothesized in this study that interferon alpha (IFN?) participates in the early stages of T1D development by triggering endoplasmic reticulum (ER) stress. To verify our hypothesis, human islets and human EndoC-?H1 cells were exposed to IFN? and tested for ER stress markers, glucose stimulated insulin secretion (GSIS) and insulin content. IFN? treatment induced upregulation of ER stress markers including Binding immunoglobulin Protein, phospho-eukaryotic translation initiation factor 2?, spliced- X-box binding protein-1, C/EBP homologous protein and activating transcription factor 4. Intriguingly, IFN? treatment did not impair GSIS but significantly decreased insulin production in both human islets and EndoC-?H1 cells. Furthermore, IFN? decreased the expression of both proinsulin convertase 1 and proinsulin convertase 2, suggesting an altered functional state of the beta cells characterized by a slower proinsulin-insulin conversion. Pretreatment of both human islets and EndoC-?H1 cells with chemical chaperones 4-phenylbutyric acid and tauroursodeoxycholic acid completely prevented IFN? effects, indicating an ER stress-mediated impairment of insulin production. We demonstrated for the first time that IFN? elicits ER stress in human beta cells providing a novel mechanistic role for this virus-induced cytokine in the development of T1D. Compounds targeting molecular processes altered in ER-stressed beta cells could represent a potential therapeutic strategy to prevent IFN?-induced beta cell dysfunction in the early onset of T1D.

SUBMITTER: Lombardi A 

PROVIDER: S-EPMC5758382 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature