Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 18 November 2020 / Approved: 19 November 2020 / Online: 19 November 2020 (15:08:41 CET)

How to cite: Andersen, P.A.K.; Petrenko, V.; Rose, P.H.; Koomen, M.; Fischer, N.; Ghiasi, S.M.; Dahlby, T.; Dibner, C.; Mandrup-Poulsen, T. 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. Preprints 2020, 2020110515 (doi: 10.20944/preprints202011.0515.v1). Andersen, P.A.K.; Petrenko, V.; Rose, P.H.; Koomen, M.; Fischer, N.; Ghiasi, S.M.; Dahlby, T.; Dibner, C.; Mandrup-Poulsen, T. 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. Preprints 2020, 2020110515 (doi: 10.20944/preprints202011.0515.v1).

Abstract

Pancreatic β-cell-specific clock knock-out 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.

Subject Areas

chronobiology; diabetes; epigenetics; immuno-metabolism; nitric oxide synthase

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