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

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.

Polycystic ovary syndrome and circulating inflammatory markers

“…McNamee and coworkers, in 2010 suggested that NA has neuroprotective properties because negatively regulates the IL-1 system. This neuroinflammation is characterized by β-adrenoceptor (46). These findings confirm the important role of SAS in the neuro-immune aspect of PCOS.…”

β2-Adrenergic receptors in immunity and inflammation: Stressing NF-κB

“…In line with this, b 2 -AR agonists have been proposed as therapeutic intervention in sepsis (reviewed by de Montmollin et al, 2009) and neurodegenerative disorders (McNamee et al, 2010;Ryan et al, 2013).…”

“…b 2 -AR activation was also recurrently associated with inhibition of the LPS-induced, NF-jB-dependent, pro-inflammatory program (IL-1b, IL-8 and TNF-a) and potentiated expression of anti-inflammatory factors (IL-1ra, IL-10 and IjBa) in cells belonging to the immune and central nervous system (Dello Russo et al, 2004;Farmer and Pugin, 2000;Herve et al, 2013;McNamee et al, 2010;O'Sullivan et al, 2009). In line with this, b 2 -AR agonists have been proposed as therapeutic intervention in sepsis (reviewed by de Montmollin et al, 2009) and neurodegenerative disorders (McNamee et al, 2010;Ryan et al, 2013).…”

Elimination of high-refined-sugar diet as treatment strategy for autistic features induced in a rodent model

“…NA has also been shown to limit neuroinflammation in the CNS [14]. This result can also be easily related to the significant elevation of IL-6, TNF α, and IFN γ in the brain homogenates of PPAtreated rats [4].…”