title: NF-κB signalling is involved in immune-modulation, but not basal functioning, of the mouse suprachiasmatic circadian clock.
abstract: Circadian rhythms are recurring near-24 hour patterns driven by an endogenous circadian timekeeping system. The master pacemaker in this system is the hypothalamic suprachiasmatic nucleus (SCN). Recently interest has been drawn to how the SCN clock responds to immune system stimulation. A major signalling component in the immune system is nuclear factor (NF)-κB. In the present study we examined the role of NF-κB in SCN function. Whilst serum shocked fibroblasts showed rhythmic nuclear localisation of p65 and p65-dependent transcription, there were no circadian changes in the SCN in expression of the NF-κB components p65, c-Rel, p-IκB or p-IKK. Chronic treatment with the NF-κB inhibitor PDTC did not impact on circadian or diurnal rhythms. Phase-shifting light pulses did not impact on SCN expression of p65, and PDTC treatment did not attenuate the behavioural or molecular response to light pulses. Peripheral treatment with lipopolysaccharide resulted in increased NF-κB component expression in the SCN. In vitro experiments with SCN slice cultures showed that treatment with NF-κB inhibitors did not markedly alter rhythmic changes in PER2::LUC expression. Further, SCN slices from nf-κb::luc mice did not show any evidence for circadian rhythms in NF-κB-mediated transcription. Experiments utilising older mice (~16 months old) showed that SCN treatment in vitro with PDTC resulted in increased amplitude of rhythmic PER2::LUC expression, and LPS treatment resulted in altered PER2::LUC rhythm acrophase. Overall, we interpret our results as providing evidence for the involvement of NF-κB in the suprachiasmatic circadian clock following immune stimulation, but not under basal conditions.
authors.affiliation: Department of Psychology, Maynooth University, National University of Ireland, John Hume Building, Maynooth, Ireland.
authors.forename: S M
authors.initials: SM
authors.lastname: O'Keeffe
authors.affiliation: Institute of Life Science, School of Medicine, Swansea University, Wales, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Beynon
authors.affiliation: Institute of Life Science, School of Medicine, Swansea University, Wales, UK.
authors.forename: J S
authors.initials: JS
authors.lastname: Davies
authors.affiliation: Department of Biology, Maynooth University, National University of Ireland, Maynooth, Ireland.
authors.forename: P N
authors.initials: PN
authors.lastname: Moynagh
authors.affiliation: Department of Psychology, Maynooth University, National University of Ireland, John Hume Building, Maynooth, Ireland.
authors.forename: A N
authors.identifier: 0000-0003-1998-0240
authors.initials: AN
authors.lastname: Coogan
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002417:Cattle; D018929:Cell Culture Techniques; D002491:Central Nervous System Agents / Q000494:pharmacology; D057906:Circadian Clocks / Q000187:drug effects / Q000502:physiology*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D003470:Culture Media; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D041681:NIH 3T3 Cells; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology*; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D010775:Photic Stimulation / Q000379:methods; D044967:Serum; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D002491:Central Nervous System Agents; D003470:Culture Media; D008070:Lipopolysaccharides; D016328:NF-kappa B; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins
keywords: NF-κB; PER2; ageing; circadian; neuroimmune; suprachiasmatic