title: Anti-inflammatory activities of fenoterol through β-arrestin-2 and inhibition of AMPK and NF-κB activation in AICAR-induced THP-1 cells.
abstract: The AMP-activated protein kinase (AMPK) pathway has been shown to be able to regulate inflammation in several cell lines. We reported that fenoterol, a β2-adrenergic receptor (β2-AR) agonist, inhibited lipopolysaccharide (LPS)-induced AMPK activation and inflammatory cytokine production in THP-1 cells, a monocytic cell line in previous studies. 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide (AICAR) is an agonist of AMPK. Whether AICAR induced AMPK activation and inflammatory cytokine production in THP-1 cells can be inhibited by fenoterol is unknown. In this study, we explored the mechanism of β2-AR stimulation with fenoterol in AICAR-induced inflammatory cytokine secretion in THP-1 cells. We studied AMPK activation using p-AMPK and AMPK antibodies, nuclear factor-kappa B (NF-κB) activation and inflammatory cytokine secretion in THP-1 cells stimulated by β2-AR in the presence or absence of AICAR and small interfering RNA (siRNA)-mediated knockdown of β-arrestin-2 or AMPKα1 subunit. AICAR-induced AMPK activation, NF-κB activation and tumor necrosis factor (TNF)-α release were reduced by fenoterol. In addition, siRNA-mediated knockdown of β-arrestin-2 abolished fenoterol's inhibition of AICAR-induced AMPK activation and TNF-α release, thus β-arrestin-2 mediated the anti-inflammatory effects of fenoterol in AICAR-treated THP-1 cells. Furthermore, siRNA-mediated knockdown of AMPKα1 significantly attenuated AICAR-induced NF-κB activation and TNF-α release, so AMPKα1 was a key signaling molecule involved in AICAR-induced inflammatory cytokine production. These data suggested that fenoterol inhibited AICAR-induced AMPK activation and TNF-α release through β-arrestin-2 in THP-1 cells. Management especially inhibition of AMPK signaling may provide new approaches and strategies for the treatments of immune diseases including inflammatory diseases and other critical illness.
authors.affiliation: Department of Infectious Diseases, Peking University Third Hospital, Hua-Yuan North Road 49, Haidian District, Beijing 100191, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Infectious Diseases, Peking University Third Hospital, Hua-Yuan North Road 49, Haidian District, Beijing 100191, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, Peking University Third Hospital, Hua-Yuan North Road 49, Haidian District, Beijing 100191, China.
authors.forename: Xiao Guang
authors.initials: XG
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, Peking University Third Hospital, Hua-Yuan North Road 49, Haidian District, Beijing 100191, China. Electronic address: xujie1998@126.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005280:Fenoterol / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D012265:Ribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000071560:beta-Arrestin 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C000605254:ARRB2 protein, human; D058666:Adrenergic beta-2 Receptor Agonists; D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012265:Ribonucleotides; D014409:Tumor Necrosis Factor-alpha; D000071560:beta-Arrestin 2; D005280:Fenoterol; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; C031143:AICA ribonucleotide
keywords: AICAR; AMPK; Fenoterol; β(2)-adrenoceptor; β-arrestin-2