Salmeterol, Agonist of β2-Aderenergic Receptor, Prevents Systemic Inflammation via Inhibiting NLRP3 Inflammasome.

In this study, we established inflammatory model in primary bone marrow-derived macrophages (BMDM) from C57BL/6J mice and β-arrestin2 knockout (β-arrestin2-/-) mice in vitro. In vivo study by LPS intraperitoneally (i.p.) in C57BL/6J mice was carried out to ascertain its roles in systemic inflammation. We found that Salmeterol (10-10 M ∼ 10-7 M) prevented the cleavage of caspase-1 and the activation of NLRP3 inflammasome, reduced the release of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in vitro. Blockade of adenosine3',5'cyclic monophosphate (cAMP) / protein kinase A (PKA) pathway with cAMP or PKA inhibitors inhibited anti-inflammatory effects of Salmeterol only at 10-7 M. Depletion of β-arrestin2 compromised the inhibitory effects of Salmeterol at both 10-10 M and 10-7 M. Salmeterol increased the interaction of β-arrestin2 and NLRP3. In vivo study showed that Salmeterol decreased the serum concentrations of pro-inflammatory cytokines IL-1β and TNF-α, blocked cleavage of caspase-1 and release of IL-1β in BMDM. These findings imply that Salmeterol at low concentrations (10-10 M ∼ 10-7 M) shows anti-inflammatory effect via inhibiting NLRP3 inflammasome. The underlying mechanisms is dosage-dependent: Salmeterol at 10-10 M shows anti-inflammatory effects through β-arrestin2 pathway, and 10-7 M Salmeterol inhibits inflammation via both classical G-protein coupled receptor (GPCR)/cAMP pathway and β-arrestin2 pathway. These...
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Tags: Biochem Pharmacol Source Type: research