McNamee, Eóin N. and Griffin, Éadaoin W. and Ryan, Karen M. and Ryan, Katie J. and Heffernan, Sheena and Harkin, Andrew and Connor, Thomas J. (2010) Noradrenaline acting at β-adrenoceptors induces expression of IL-1β and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex. Neuropharmacology, 59. pp. 37-48. ISSN 1873-7064

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Abstract

Evidence indicates that noradrenaline elicits anti-inflammatory actions in the central nervous system (CNS), and plays a neuroprotective role where inflammatory events contribute to pathology. Here we examined the ability of pharmacological enhancement of central noradrenergic tone to impact upon activation of the IL-1 system in rat brain. Treatment with the noradrenaline reuptake inhibitor reboxetine combined with the α2-adrenoceptor antagonist idazoxan induced expression of IL-1β as well as its negative regulators, IL-1 receptor antagonist (IL-1ra) and IL-1 type II receptor (IL-1RII) in rat cortex. The ability of reboxetine/idazoxan treatment to activate the IL-1 system was mediated by β-adrenoceptors, as the aforementioned effects were blocked by the β-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant β2-adrenoceptor agonist clenbuterol induced expression of IL-1β, IL-1ra and IL-1RII in rat brain. This action was selective to the IL-1 system, as other inflammatory cytokines including TNF-α, IL-6 or IFN-γ were not induced by clenbuterol. Induction of IL-1β was accompanied by activation of NFκB and of the MAP kinase ERK, and clenbuterol also induced expression of the IL-1β-inducible gene CINC-1. The ability of clenbuterol to activate the IL-1 system was blocked by propranolol, and was mimicked by the highly selective β2-adrenoceptor agonist formoterol. Despite the ability of clenbuterol to activate the central IL-1 system, it largely combated the neuroinflammatory response induced by systemic inflammatory stimulus (bacterial lipopolysaccharide; LPS). Specifically, whilst the ability of clenbuterol to induce expression of IL-1RII and IL-1Ra was maintained following the inflammatory challenge, its ability to induce IL-1β was reduced. In addition, clenbuterol suppressed LPS-induced expression of the inflammatory cytokines TNF-α and IL-6, the inflammatory chemokines RANTES and IP-10, the co-stimulatory molecules CD40 and ICAM-1. Thus overall, clenbuterol suppresses the innate inflammatory response in rat brain.

Item Type:	Article
Keywords:	Noradrenaline; β-adrenoceptors; IL-1; IL-1ra; IL-1RII; Neuroinflammation; LPS;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	12601
Identification Number:	https://doi.org/10.1016/j.neuropharm.2010.03.014
Depositing User:	Eoin McNamee
Date Deposited:	24 Mar 2020 12:45
Journal or Publication Title:	Neuropharmacology
Publisher:	Elsevier
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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