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Regulation of the β-cell inflammasome and contribution to stress-induced cellular dysfunction and apoptosis

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  1. Progressive changes in human follicular fluid composition over the course of ovulation: quantitative proteomic analyses

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  2. Human granulosa cells function as innate immune cells executing an inflammatory reaction during ovulation: a microarray analysis

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  3. Identification of circulating small non-coding RNAs in relation to male subfertility and reproductive hormones

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  4. Experimental models of testicular development and function using human tissue and cells

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  1. Development of depression in patients with oral cavity cancer: a systematic review

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  2. Impact of surgical resection margins less than 5 mm in oral cavity squamous cell carcinoma: a systematic review

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  3. Association between head and neck cancer and sexually transmitted diseases: a Danish nationwide, case-control study

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  4. Circulating tumour DNA alterations as biomarkers for head and neck cancer: a systematic review

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β-Cells may be a source of IL-1β that is produced as inactive pro-IL-1β and processed into biologically-active IL-1β by enzymatic cleavage mediated by the NLRP1-, NLRP3- and NLRC4-inflammasomes. Little is known about the β-cell inflammasomes. NLRP1-expression was upregulated in islet-cells from T2D-patients and by IL-1β+IFNγ in INS-1 cells in a histone-deacetylase dependent manner. NLRP3 was downregulated by cytokines in INS-1 cells. NLRC4 was barely expressed and not regulated by cytokines. High extracellular K+ reduced cytokine-induced apoptosis and NO production and restored cytokine-inhibited accumulated insulin-secretion. Basal inflammasome expression was JNK1-3 dependent. Knock-down of the ASC interaction domain common for NLRP1 and 3 improved insulin secretion and ameliorated IL-1β and/or glucolipotoxicity-induced cell death and reduced cytokine-induced NO-production. Broad inflammasome-inhibition, but not NLRP3-selective inhibition, protected against IL-1β-induced INS-1 cell-toxicity. We suggest that IL-1β causes β-cell toxicity in part by NLRP1 mediated caspase-1-activation and maturation of IL-1β leading to an autocrine potentiation loop.

Original languageEnglish
JournalMolecular and Cellular Endocrinology
Volume478
Pages (from-to)106-114
Number of pages9
ISSN0303-7207
DOIs
Publication statusPublished - 15 Dec 2018

    Research areas

  • Animals, Apoptosis/drug effects, CARD Signaling Adaptor Proteins, Cell Death/drug effects, Cell Line, Cytokines/pharmacology, Cytoprotection/drug effects, Female, Glucose/toxicity, Histone Deacetylases/metabolism, Humans, Inflammasomes/metabolism, Insulin Secretion/drug effects, Insulin-Secreting Cells/drug effects, Interleukin-1beta/metabolism, JNK Mitogen-Activated Protein Kinases/metabolism, Lipids/toxicity, Middle Aged, Potassium/pharmacology, RNA, Messenger/genetics, Rats, Receptors, Purinergic P2X7/metabolism, Stress, Physiological/drug effects, Young Adult

ID: 59692775