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.