Noradrenaline acting at central β-adrenoceptors induces interleukin-10 and suppressor of cytokine signaling-3 expression in rat brain: Implications for neurodegeneration

• Published in: Brain, behavior, and immunity behavior, and immunity, 2010-05, Vol.24 (4), p.660-671
• Main Authors: McNamee, Eoin N, Ryan, Karen M, Griffin, Éadaoin W, González-Reyes, Rodrigo E, Ryan, Katie J, Harkin, Andrew, Connor, Thomas J
• Format: Article
• Language: English
• Subjects: Adrenergic alpha-Antagonists - administration & dosage; Adrenergic alpha-Antagonists - pharmacology; Adrenergic beta-Agonists - administration & dosage; Adrenergic beta-Agonists - pharmacology; Adrenergic beta-Antagonists; Adrenergic Uptake Inhibitors - administration & dosage; Adrenergic Uptake Inhibitors - pharmacology; Allergy and Immunology; Animals; Anti-inflammatory; Brain; Brain - drug effects; Brain - immunology; Brain - metabolism; Cerebral Cortex - immunology; Clenbuterol - administration & dosage; Clenbuterol - pharmacology; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hippocampus - immunology; Idazoxan - administration & dosage; Idazoxan - pharmacology; IL-10; Injections, Intraperitoneal; Interleukin-10 - immunology; Interleukin-10 - metabolism; Interleukin-4 - genetics; Interleukin-4 - metabolism; Male; Morpholines - administration & dosage; Morpholines - pharmacology; Noradrenaline; Norepinephrine - immunology; Norepinephrine - pharmacology; Phosphorylation - drug effects; Propranolol - administration & dosage; Propranolol - pharmacology; Psychiatry; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta - classification; Receptors, Adrenergic, beta - drug effects; Receptors, Adrenergic, beta - metabolism; Receptors, Adrenergic, beta-2; Signal Transduction - drug effects; SOCS3; STAT3; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; β-Adrenoceptor
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2010.02.005

Abstract Evidence indicates that the monoamine neurotransmitter noradrenaline elicits anti-inflammatory actions in the central nervous system (CNS), and consequently may play a neuroprotective role where inflammatory events contribute to CNS pathology. Here we examined the ability of pharmacologically enhancing central noradrenergic tone to induce expression of anti-inflammatory cytokines in rat brain. Administration of the noradrenaline reuptake inhibitor reboxetine (15 mg/kg; ip) combined with the α2 -adrenoceptor antagonist idazoxan (1 mg/kg; ip) induced interleukin-10 (IL-10) expression in rat cortex and hippocampus. In addition, these drug treatments induced IL-10 signaling as indicated by increased STAT3 phosphorylation and suppressor of cytokine signaling-3 (SOCS-3) mRNA expression. In contrast to the profound increase in IL-10 induced by the reboxetine/idazoxan combination, the other two broad spectrum anti-inflammatory cytokines IL-4 and TGF-β were not induced by this treatment. The ability of combined treatment with reboxetine and idazoxan to induce IL-10 and SOCS3 expression was mediated by β-adrenoceptor activation, as their induction was blocked by pre-treatment with the β-adrenoceptor antagonist propranolol. Moreover, administration of the brain penetrant β2 -adrenoceptor agonist clenbuterol induced a time- and dose-dependent increase in central IL-10 and SOCS3 expression, and the ability of clenbuterol to induce IL-10 and SOCS-3 expression was blocked by the centrally acting β-adrenoceptor antagonist, propranolol, and was mimicked by the highly selective β2 -adrenoceptor agonist formoterol. In all, these data indicate that increasing central noradrenergic tone induces IL-10 production and signaling in the CNS, which may protect against neurodegeneration.