Noradrenaline acting at beta-adrenoceptors induces expression of IL-1beta and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex
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2010Citation:
E.N. McNamee, E.W. Griffin, K.M. Ryan, K.J. Ryan, S. Heffernan, A. Harkin and T.J. Connor, Noradrenaline acting at beta-adrenoceptors induces expression of IL-1beta and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex, Neuropharmacology, 59, 1-2, 2010, 37 - 48Download Item:
Noradrenaline acting at ?-adrenoceptors induces expression of IL-1? and its negative regulators IL-1ra and IL-1RII, and drives an overall anti-inflammatory phenotype in rat cortex.pdf (Accepted for publication (author's copy) - Peer Reviewed) 1.181Mb
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 ?2-adrenoceptor antagonist idazoxan induced expression of IL-1? as well as its negative regulators, IL-1 receptor antagonist (IL-1ra) and IL-1type II receptor (IL-1RII) in rat cortex. The ability of reboxetine/idazoxan treatment to activate the IL-1 system was mediated by ?-adrenoceptors, as the aforementioned effects were blocked by the ?-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant ?2-adrenoceptor agonist clenbuterol induced expression of IL-1?, IL-1ra and IL-1RII in rat brain. This action was selective to the IL-1 system, as other inflammatory cytokines including TNF-?, IL-6 or IFN-? were not induced by clenbuterol. Induction of IL-1? was accompanied by activation of NF?B and of the MAP kinase ERK, and clenbuterol also induced expression of the IL-1?-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 ?2-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-1? was reduced. In addition, clenbuterol suppressed LPS-induced expression of the inflammatory cytokines TNF-? 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.
Author's Homepage:
http://people.tcd.ie/connorthttp://people.tcd.ie/aharkin
http://people.tcd.ie/griffie
http://people.tcd.ie/kryan7
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Neuropharmacology59
1-2
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Noradrenaline, ?-adrenoceptor, IL-1, IL-1ra, IL-1RII, neuroinflammation, LPSLicences: