Fenoterol inhibits LPS-induced AMPK activation and inflammatory cytokine production through β-arrestin-2 in THP-1 cell line

The AMP-activated protein kinase (AMPK) pathway is involved in regulating inflammation in several cell lines. We reported that fenoterol, a beta(2)-adrenergic receptor (beta(2)-AR) agonist, had anti-inflammatory effects in THP-1 cells, a monocytic cell line. Whether the fenoterol anti-inflammatory effect involves the AMPK pathway is unknown. In this study, we explored the mechanism of beta(2)-AR stimulation with fenoterol in a lipopolysaccharide (LPS)-induced inflammatory cytokine secretion in THP-1 cells. We studied whether fenoterol and beta-arrestin-2 or AMPK alpha l subunit knockdown could affect LPS-induced AMPK activation, nuclear factor-kappa B (NF-kappa B) activation and inflammatory cytokine secretion. LPS-induced AMPK activation and interleukin 1 beta (IL-1 beta) release were reduced with fenoterol pretreatment of THP-1 cells. SiRNA knockdown of beta-arrestin-2 abolished the fenoterol inhibition of LPS-induced AMPK activation and interleukin 1 beta (IL-1 beta) release, thus beta-arrestin-2 mediated the anti-inflammatory effects of fenoterol on LPS-treated THP-1 cells. In addition, siRNA knockdown of AMPK alpha 1 significantly attenuated the LPS-induced NF-kappa B activation and IL-1 beta release, so AMPKal was a key signaling molecule involved in LPS-induced inflammatory cytokine production. These results suggested the beta(2)-AR agonist fenoterol inhibited LPS-induced AMPK activation and IL-1 beta release via beta-arrestin-2 in THP-1 cells. The exploration of these mechanisms may help optimize therapeutic agents targeting these pathways in inflammatory diseases. (C) 2015 Elsevier Inc. All rights reserved.