Azithromycin inhibits MUC5AC production induced by the Pseudomonas aeruginosa autoinducer N-(3-Oxododecanoyl) homoserine lactone in NCI-H292 Cells.
The features of chronic airway diseases, including chronic bronchitis, cystic fibrosis, bronchiectasis, and diffuse panbronchiolitis, include chronic bacterial infection and airway obstruction by mucus. Pseudomonas aeruginosa is one of the most common pathogens in chronic lung infection, and quorum-sensing systems contribute to the pathogenesis of this disease. The quorum-sensing signal molecule [N-(3-oxododecanoyl) homoserine lactone (3O-C(12)-HSL)] not only regulates bacterial virulence but also is associated with the immune response. In this study, we investigated whether 3O-C(12)-HSL could stimulate the production of a major mucin core protein, MUC5AC. The effect of a macrolide on MUC5AC production was also studied. 3O-C(12)-HSL induced NCI-H292 cells to express MUC5AC at both the mRNA and the protein levels in time- and dose-dependent manners. A 15-membered macrolide, azithromycin, inhibited MUC5AC production that was activated by 3O-C(12)-HSL. 3O-C(12)-HSL induced extracellular signal-regulated kinase (ERK) 1/2 and I-kappa B phosphorylation in cells, and this induction was suppressed by azithromycin. 3O-C(12)-HSL-induced MUC5AC production was blocked by the ERK pathway inhibitor PD98059. Our findings suggest that the P. aeruginosa autoinducer 3O-C(12)-HSL contributes to excessive mucin production in chronic bacterial infection. Azithromycin seems to reduce this mucin production by interfering with intracellular signal transduction.
Second Department of Internal Medicine, School of Medicine, Nagasaki University, Nagasaki 852-8501, Japan.
Yoshifumi
Y
Imamura
Katsunori
K
Yanagihara
Yohei
Y
Mizuta
Masafumi
M
Seki
Hideaki
H
Ohno
Yasuhito
Y
Higashiyama
Yoshitsugu
Y
Miyazaki
Kazuhiro
K
Tsukamoto
Yoichi
Y
Hirakata
Kazunori
K
Tomono
Jun-ichi
J
Kadota
Shigeru
S
Kohno
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D006714:Homoserine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D055271:Mucin 5AC; D009077:Mucins / Q000096:biosynthesis*; D010766:Phosphorylation; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D000900:Anti-Bacterial Agents; D005419:Flavonoids; D020672:I-kappa B Proteins; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D009077:Mucins; C109860:N-(3-oxododecanoyl)homoserine lactone; D006714:Homoserine; D017963:Azithromycin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D015107:4-Butyrolactone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one