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Azithromycin induces sestrin2 expression through Nrf2 signaling pathway in lung epithelial cells stimulated with cigarette smoke extract (869.11)
Author(s) -
Yang Yu,
Cuevas Santiago,
Armando Ines,
Jose Pedro
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.869.11
Subject(s) - azithromycin , reactive oxygen species , intracellular , antioxidant , chemistry , oxidative stress , gene knockdown , pharmacology , biochemistry , biology , antibiotics , gene
Azithromycin has been reported to reduce exacerbation of chronic obstructive pulmonary disease (COPD) based on its antioxidant and anti‐inflammatory effects. The aim of this study was to identify the underlying molecular mechanisms. We found that decreased intracellular Nrf2 protein level (‐55±6%) and downstream target NQO1 (‐45±4%), increased reactive oxygen species (ROS) production (1.6‐fold) and interleukin 8 (IL‐8) secretion (2.1‐fold) in A549 cells exposed to cigarette smoke extract (CSE) (200ug/ml, 24h). Pretreatment with azithromycin (5µg/ml) suppressed ROS production (‐29±4%) and IL‐8 (‐45±6%) induced by CSE. Furthermore, azithromycin promoted Nrf2 nuclear translocation. Sestrin2, an antioxidant enzyme, was increased after azithromycin treatment in a time and concentration dependent manner. Additionally, azithromycin reduced hyper‐oxidized peroxiredoxins, the downstream target of sestrin2. Knockdown of Nrf2 resulted in suppression of azithromycin‐induced sestrin2 expression (‐35±3%). Silencing sestrin2 abolished azithromycin‐induced decrease in peroxiredoxins hyper‐oxidation and partially attenuated the inhibitory effect of azithromycin on ROS production and IL‐8 expression (by 26% and 41%, respectively). Our results suggest that one of the antioxidant and anti‐inflammatory effects of azithromycin in COPD may be, in part, mediated by induction of sestrin2 via Nrf2. Grant Funding Source : HL068686