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 β2-adrenergic receptor (β2-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 β2-AR stimulation with fenoterol in a lipopolysaccharide (LPS)-induced inflammatory cytokine secretion in THP-1 cells. We studied whether fenoterol and β-arrestin-2 or AMPKα1 subunit knockdown could affect LPS-induced AMPK activation, nuclear factor-kappa B (NF-κB) activation and inflammatory cytokine secretion. LPS-induced AMPK activation and interleukin 1β (IL-1β) release were reduced with fenoterol pretreatment of THP-1 cells. SiRNA knockdown of β-arrestin-2 abolished the fenoterol inhibition of LPS-induced AMPK activation and interleukin 1β (IL-1β) release, thus β-arrestin-2 mediated the anti-inflammatory effects of fenoterol on LPS-treated THP-1 cells. In addition, siRNA knockdown of AMPKα1 significantly attenuated the LPS-induced NF-κB activation and IL-1β release, so AMPKα1 was a key signaling molecule involved in LPS-induced inflammatory cytokine production. These results suggested the β2-AR agonist fenoterol inhibited LPS-induced AMPK activation and IL-1β release via β-arrestin-2 in THP-1 cells. The exploration of these mechanisms may help optimize therapeutic agents targeting these pathways in inflammatory diseases.
Department of Respiratory Medicine, Peking University Third Hospital, Beijing, People's Republic of China; Department of Infectious Diseases, Peking University Third Hospital, Beijing, People's Republic of China.
Wei
W
Wang
Department of Respiratory Medicine, Peking University Third Hospital, Beijing, People's Republic of China.
Yuan
Y
Zhang
Department of Institute of Vascular Medicine and Beijing Key Laboratory of Cardiovascular Receptors Research, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University Third Hospital, Beijing, People's Republic of China.
Ming
M
Xu
Department of Institute of Vascular Medicine and Beijing Key Laboratory of Cardiovascular Receptors Research, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University Third Hospital, Beijing, People's Republic of China.
You-Yi
YY
Zhang
Department of Respiratory Medicine, Peking University Third Hospital, Beijing, People's Republic of China. Electronic address: puh3_hb@bjmu.edu.cn.
Bei
B
He
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D019390:Arrestins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D005280:Fenoterol / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; D058666:Adrenergic beta-2 Receptor Agonists; D019390:Arrestins; D016207:Cytokines; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D034741:RNA, Small Interfering; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D005280:Fenoterol; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human
AMPK; Fenoterol; Lipopolysaccharide; THP-1 cell line; β(2)-adrenergic receptor; β-arrestin-2