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摘要
The prevalence of obesity and type 1 diabetes in children is increasing worldwide. Insulin resistance and augmented circulating free fatty acids associated with obesity may cause pancreatic beta-cell endoplasmic reticulum (ER) stress. We tested the hypothesis that mild ER stress predisposes beta-cells to an exacerbated inflammatory response when exposed to IL-1 beta or TNF-alpha, cytokines that contribute to the pathogenesis of type 1 diabetes. INS-1E cells or primary rat beta-cells were exposed to a low dose of the ER stressor cyclopiazonic acid (CPA) or free fatty acids, followed by low-dose IL-1 beta or TNF-alpha. ER stress signaling was inhibited by small interfering RNA. Cells were evaluated for proinflammatory gene expression by RT-PCR and ELISA, gene reporter activity, p65 activation by immunofluorescence, and apoptosis. CPA pretreatment enhanced IL-1 beta- induced, but not TNF-alpha-induced, expression of chemokine (C-C motif) ligand 2, chemokine (C-X-C motif) ligand 1, inducible nitric oxide synthase, and Fas via augmented nuclear factor kappa B (NF-kappa B) activation. X-box binding protein 1 (XBP1) and inositol-requiring enzyme 1, but not CCAAT/enhancer binding protein homologous protein, knockdown prevented the CPA-induced exacerbation of NF-kappa B-dependent genes and decreased IL-1 beta-induced NF-kappa B promoter activity. XBP1 modulated NF-kappa B activity via forkhead box O1 inhibition. In conclusion, rat beta-cells facing mild ER stress are sensitized to IL-1 beta, generating a more intense and protracted inflammatory response through inositol-requiring enzyme 1/XBP1 activation. These observations link beta-cell ER stress to the triggering of exacerbated local inflammation. (Endocrinology 153: 3017-3028, 2012)
- 出版日期2012-7
