Melatonin inhibits MUC5AC production via suppression of MAPK signaling in human airway epithelial cells.
Mucus acts as a primary defense system in the airway against various stimuli. However, excess mucus production causes a reduction in lung function via limitation of the airflow in the airway of patients suffering from asthma or chronic obstructive pulmonary disease (COPD). In this study, we evaluated the effects of melatonin on the production of MUC5AC, a major constituent of the mucin that is secreted from the airway, using epidermal growth factor (EGF)-stimulated NCI-H292 cells, a human mucoepidermoid carcinoma cell line, and an ovalbumin (OVA)-induced asthma murine model. Melatonin treatment significantly reduced the mRNA and protein levels of MUC5AC and reduced interleukin (IL)-6 production in EGF-stimulated H292 cells. Melatonin markedly decreased the phosphorylation of MAPKs, including ERK1/2, JNK, and p-38, induced by EGF stimulation. These findings were consistent with the results using MAPK inhibitors. Particularly, co-treatment with melatonin and a MAPK inhibitor more effectively suppressed MAPK phosphorylation than treatment with a MAPK inhibitor alone, which resulted in a reduction in MUC5AC expression. In the asthma murine model, melatonin-treated mice exhibited a marked reduction in MUC5AC expression in the airway compared with the OVA-induced mice. These reductions were accompanied by reductions in proinflammatory cytokine production and inflammatory cell infiltration. Collectively, these findings indicate that melatonin effectively inhibits MUC5AC expression. These effects may be closely associated with the inhibition of MAPK phosphorylation. Furthermore, our study suggests that melatonin could represent a potential therapeutic for chronic airway diseases, such as asthma and COPD.
Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Chungbuk, Korea; College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.
In-Sik
IS
Shin
Ji-Won
JW
Park
Na-Rae
NR
Shin
Chan-Mi
CM
Jeon
Ok-Kyoung
OK
Kwon
Mee-Young
MY
Lee
Hui-Seong
HS
Kim
Jong-Choon
JC
Kim
Sei-Ryang
SR
Oh
Kyung-Seop
KS
Ahn
D000818:Animals; D001249:Asthma / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020935:MAP Kinase Signaling System; D008550:Melatonin / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D055271:Mucin 5AC / Q000096:biosynthesis*; D010766:Phosphorylation; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology
C524678:MUC5AC protein, human; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D048049:Extracellular Signal-Regulated MAP Kinases; D008550:Melatonin
MAPKs; MUC5AC; NCI-H292; asthma; melatonin