• Free Radic. Biol. Med. · May 2020

    Erythromycin reverses cigarette smoke extract-induced corticosteroid insensitivity by inhibition of the JNK/c-Jun pathway.

    • Yan-Fei Bin, Nan Ma, Yan-Xiu Lu, Xue-Jiao Sun, Yi Liang, Jing Bai, Jian-Quan Zhang, Mei-Hua Li, Xiao-Ning Zhong, and Zhi-Yi He.
    • Department of Respiratory and Critical Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China.
    • Free Radic. Biol. Med. 2020 May 20; 152: 494-503.

    AbstractCorticosteroid insensitivity is a feature of airway inflammation in chronic obstructive pulmonary disease (COPD). Erythromycin exhibits anti-inflammatory activity in COPD, but the concrete mechanism is still unclear. This study aimed to investigate the effects of erythromycin on corticosteroid sensitivity in peripheral blood mononuclear cells (PBMCs) and U937 cells (a human monocytic cell line). PBMCs were collected from non-smokers, healthy smoker volunteers, and COPD subjects. U937 cells were incubated with or without erythromycin and stimulated with TNF-α in the presence or absence of cigarette smoke extract (CSE). The dexamethasone (Dex) concentration required to achieve 50% inhibition of TNF-α-induced interleukin (IL)-8 production was determined and the mitogen-activated protein kinase (MAPK)/Activator protein-1 (AP-1) pathway was also evaluated. Erythromycin improved corticosteroid sensitivity in PBMCs obtained from COPD patients and CSE-treated U937 cells. This improvement in corticosteroid sensitivity was associated with reduced c-Jun expression, which resulted from the inhibition of P38 Mitogen-activated protein kinase (P38MAPK), extracellular signal-regulated protein kinase (ERK)1/2, and c-Jun N-terminal kinase (JNK) phosphorylation. Erythromycin had no effects on the phosphorylated and total protein expression levels of P38MAPK and ERK; however, it induced inhibition of the phosphorylated and total protein expression levels of JNK. This study provides evidence that erythromycin restores corticosteroid sensitivity in PBMCs and U937 cells. JNK inhibition by erythromycin restores corticosteroid sensitivity via the inhibition of c-Jun expression. Thus, JNK/c-Jun is a potential novel therapeutic target for COPD.Copyright © 2019. Published by Elsevier Inc.

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