Noradrenergic modulation of the central nervous system immune response : a critical role for the Beta-adrenoceptor

Abstract

Evidence suggests that inflammation is a significant contributor to pathology in a number of neurodegenerative disease states. In this regard, the pro-inflammatory cytokine interleukin-1β (IL-1β) plays a key role in initiating an immune response within the central nervous system (CNS). However in addition to evidence indicating that IL-1β has detrimental effects for neuronal survival, other studies indicate that IL-1 can be neuroprotective possibly via induction of neurotrophic factors. The actions of IL-1β can be regulated by interleukin-1 receptor antagonist (IL-1ra), an endogenously produced antagonist that prevents IL-1β from acting on the IL-1 type I receptor [IL-IR(I)]. Consequently, the balance between IL-1ra/IL-1β is considered to be of pathological importance, and pharmacological strategies that tip the balance in favour of IL-Ira may be of therapeutic benefit in situations where IL-1β contributes to pathology. Evidence is emerging to suggest that the neurotransmitter noradrenaline elicits anti-inflammatory actions in the CNS, and consequently may play an endogenous neuroprotective role. Here we report that noradrenaline induces production of secreted IL-Ira from primary rat cortical mixed glial cells. This noradrenaline-induced increase in IL-Ira production is mediated via β-adrenoceptor activation, and downstream signaling via the cAMP-Protein Kinase A pathway and also requires activation of the MAP kinase ERK. In addition to increasing IL-Ira, noradrenaline increased expression of the IL-1type II receptor [IL-IR(II)]; a decoy receptor that serves to sequester IL-1β. The ability of noradrenaline to induce IL-1 R(ll) expression was also mediated via β-adrenoceptor activation and downstream signaling via Protein Kinase A and ERK. In parallel with its ability to increase IL-Ira and IL-IR(II) expression, noradrenaline prevented the neurotoxicity induced by conditioned medium from IL-1β-treated mixed glial cells. Considering the pivotal role played by IL-1β in neuroinflammation, the ability of noradrenaline to negatively regulate the IL-1 system and protect against IL-1β - induced neurotoxicity may be of therapeutic relevance in neurodegenerative disorders where inflammation contributes to pathology.