title: 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.
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 alpha(2)-adrenoceptor antagonist idazoxan induced expression of IL-1beta 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 beta-adrenoceptors, as the aforementioned effects were blocked by the beta-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant beta(2)-adrenoceptor agonist clenbuterol induced expression of IL-1beta, IL-1ra and IL-1RII in rat brain. This action was selective to the IL-1 system, as other inflammatory cytokines including TNF-alpha, IL-6 or IFN-gamma were not induced by clenbuterol. Induction of IL-1beta was accompanied by activation of NFkappaB and of the MAP kinase ERK, and clenbuterol also induced expression of the IL-1beta-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 beta(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-1beta was reduced. In addition, clenbuterol suppressed LPS-induced expression of the inflammatory cytokines TNF-alpha 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.
authors.affiliation: Trinity College Institute of Neuroscience, Department of Physiology, School of Medicine, Trinity College, Dublin, Ireland.
authors.forename: Eoin N
authors.initials: EN
authors.lastname: McNamee
authors.forename: Eadaoin W
authors.initials: EW
authors.lastname: Griffin
authors.forename: Karen M
authors.initials: KM
authors.lastname: Ryan
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Ryan
authors.forename: Sheena
authors.initials: S
authors.lastname: Heffernan
authors.forename: Andrew
authors.initials: A
authors.lastname: Harkin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Connor
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002976:Clenbuterol / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D008297:Male; D015213:Neuroimmunomodulation / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D053574:Receptors, Interleukin-1 Type II / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D016207:Cytokines; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D011943:Receptors, Adrenergic, beta; D018343:Receptors, Adrenergic, beta-2; D053574:Receptors, Interleukin-1 Type II; D009638:Norepinephrine; D002976:Clenbuterol