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

Phillip Alexander Keller Andersen, Volodymyr Petrenko, Peter Horskjær Rose, Melissa Koomen, Nico Fischer, Seyed Mojtaba Ghiasi, Tina Dahlby, Charna Dibner, Thomas Mandrup-Poulsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

8 Citations (Scopus)
32 Downloads (Pure)

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 un-der-investigated. Real-time recording of Per2:luciferase reporter activity in murine and human pancreatic islets demonstrated that the proinflammatory cytokine interleukin-1β (IL-1β) length-ened 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 cyto-kine-mediated increases in clock gene expression. In conclusion, the cytokine-combination per-turbed 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.

Original languageEnglish
Article number83
JournalInternational Journal of Molecular Sciences
Volume22
Issue number1
Pages (from-to)1-25
ISSN1661-6596
DOIs
Publication statusPublished - 2021

Bibliographical note

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Chronobiology
  • Diabetes
  • Epigenetics
  • Immuno-metabolism
  • Nitric oxide synthase

Cite this