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JAC Advance Access originally published online on October 18, 2008
Journal of Antimicrobial Chemotherapy 2009 63(1):109-114; doi:10.1093/jac/dkn427
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Different effects of telithromycin on MUC5AC production induced by human neutrophil peptide-1 or lipopolysaccharide in NCI-H292 cells compared with azithromycin and clarithromycin

Hiroshi Ishimoto1, Hiroshi Mukae1,*, Noriho Sakamoto1, Misato Amenomori1, Takeshi Kitazaki1, Yoshifumi Imamura1, Hanako Fujita1, Hiroshi Ishii2, Seiko Nakayama1, Katsunori Yanagihara3 and Shigeru Kohno1

1 Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan 2 Department of Infectious Diseases, Oita University Faculty of Medicine, Oita, Japan 3 Department of Laboratory Medicine, Nagasaki University School of Medicine, Nagasaki, Japan

Received 23 April 2008; returned 3 July 2008; revised 7 September 2008; accepted 18 September 2008

* Corresponding author. Tel: +81-95-819-7273; Fax: +81-95-849-7285; E-mail: hmukae{at}net.nagasaki-u.ac.jp

Objectives: Mucus hypersecretion is a prominent feature in patients with chronic respiratory tract infections such as cystic fibrosis and diffuse panbronchiolitis, and the clinical effectiveness of macrolide antibiotics has been reported in these patients. Because human neutrophil peptide-1 (HNP-1), an antimicrobial peptide in neutrophils, exists in high concentrations in the airway fluid of these patients, we examined the direct effect of HNP-1 on MUC5AC mucin production using NCI-H292 cells. The effects of macrolide antibiotics on the response were also examined.

Methods: MUC5AC synthesis was assayed using RT–PCR and ELISA. Phosphorylation of ERK1/2 was determined by western blotting.

Results: Stimulation with HNP-1 or lipopolysaccharide (LPS) derived from Pseudomonas aeruginosa increases the production of MUC5AC mRNA and protein, and an additive effect was found upon co-stimulation with both HNP-1 and LPS. Azithromycin and clarithromycin had inhibitory effects on overproduction of MUC5AC induced by HNP-1 or LPS stimulation. Telithromycin also had an inhibitory effect on MUC5AC production induced by LPS, but not on production by HNP-1. Phosphorylation of ERK1/2 was induced by HNP-1 or LPS stimulation, and azithromycin, clarithromycin and telithromycin had inhibitory effects on ERK1/2 phosphorylation induced by LPS, but not by HNP-1.

Conclusions: These findings suggest that neutrophil-derived defensins as bacterial components contribute to excessive mucus production in patients with respiratory tract infections, and that macrolide and ketolide antibiotics directly inhibit these actions by interfering with intracellular signal transduction. However, the mechanism of telithromycin inhibition of MUC5AC synthesis may differ from the response induced by azithromycin and clarithromycin.

Keywords: HNP-1 , LPS , macrolide antibiotics , ERK1/2 phosphorylation


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