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Title

Proinflammatory cytokines perturb mouse and human pancreatic islet circadian rhythmicity and induce uncoordinated β-cell clock gene expression via nitric oxide, lysine deacetylases, and immunoproteasomal activity

Authors
Andersen, Phillip Alexander Keller
Rose, Peter Horskjær
Koomen, Melissa
Fischer, Nico
Ghiasi, Seyed Mojtaba
Dahlby, Tina
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Published in International Journal of Molecular Sciences. 2020, vol. 22, no. 1, 83
Abstract Pancreatic β-cell-specific clock knockout mice develop β-cell oxidative-stress and failure, as well as glucose-intolerance. How inflammatory stress affects the cellular clock is under-investigated. Real-time recording of Per2:luciferase reporter activity in murine and human pancreatic islets demonstrated that the proinflammatory cytokine interleukin-1β (IL-1β) lengthened the circadian period. qPCR-profiling of core clock gene expression in insulin-producing cells suggested that the combination of the proinflammatory cytokines IL-1β and interferon-γ (IFN-γ) caused pronounced but uncoordinated increases in mRNA levels of multiple core clock genes, in particular of reverse-erythroblastosis virus α (Rev-erbα), in a dose- and time-dependent manner. The REV-ERBα/β agonist SR9009, used to mimic cytokine-mediated Rev-erbα induction, reduced constitutive and cytokine-induced brain and muscle arnt-like 1 (Bmal1) mRNA levels in INS-1 cells as expected. SR9009 induced reactive oxygen species (ROS), reduced insulin-1/2 (Ins-1/2) mRNA and accumulated- and glucose-stimulated insulin secretion, reduced cell viability, and increased apoptosis levels, reminiscent of cytokine toxicity. In contrast, low (<5,0 μM) concentrations of SR9009 increased Ins-1 mRNA and accumulated insulin-secretion without affecting INS-1 cell viability, mirroring low-concentration IL-1β mediated β-cell stimulation. Inhibiting nitric oxide (NO) synthesis, the lysine deacetylase HDAC3 and the immunoproteasome reduced cytokine-mediated increases in clock gene expression. In conclusion, the cytokine-combination perturbed the intrinsic clocks operative in mouse and human pancreatic islets and induced uncoordinated clock gene expression in INS-1 cells, the latter effect associated with NO, HDAC3, and immunoproteasome activity.
Keywords ARNTL Transcription Factors/genetics/metabolismAnimalsCell LineTumorCellsCulturedCircadian RhythmFemaleHEK293 CellsHistone Deacetylases/metabolismHumansInsulin/metabolismInsulin-Secreting Cells/drug effects/metabolismInterferon-gamma/metabolism/pharmacologyMaleMiceNitric Oxide/metabolismProteasome Endopeptidase Complex/metabolismReactive Oxygen Species/metabolism
Identifiers
PMID: 33374803
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Appendix (791 Kb) - public document Free access
Other version: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795908/
Structures
Research group Endocrinologie et horloge circadienne (948)
Projects
Swiss National Science Foundation: 31003A_166700
Swiss National Science Foundation: 310030_184708
Autre: Independent Research Fund Denmark (grant# 8020-00359B)
Citation
(ISO format)
ANDERSEN, Phillip Alexander Keller et al. Proinflammatory cytokines perturb mouse and human pancreatic islet circadian rhythmicity and induce uncoordinated β-cell clock gene expression via nitric oxide, lysine deacetylases, and immunoproteasomal activity. In: International Journal of Molecular Sciences, 2020, vol. 22, n° 1, p. 83. doi: 10.3390/ijms22010083 https://archive-ouverte.unige.ch/unige:154823

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Deposited on : 2021-09-20

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