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

Abstract

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.

Systemic upregulation of neutrophil -defensins and serine proteases in neutrophilic asthma

“…19 20 a-defensin-1 can increase mucin gene and protein expression, which may contribute to excess mucus production. 21 High levels of a-defensins in airway secretions have been reported in respiratory conditions such as cystic fibrosis, 22 idiopathic pulmonary fibrosis and acute respiratory distress syndrome. 23 Deficiency of a 1 -antitrypsin is a condition whereby neutrophil proteases and a-defensins are elevated simultaneously.…”

Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

“…NF-B activation was inhibited and apoptosis was increased in both cell lines by use of telithromycin (164). Telithromycin, as well as azithromycin and clarithromycin, can inhibit the increased production of MUC5AC mRNA and protein in NCI-H292 cells stimulated with LPS (108). However, telithromycin did not inhibit MUC5AC production induced by human neutrophil peptide-1 (HNP-1), while azithromycin and clarithromycin did inhibit MUC5AC.…”

Macrolides Inhibit Fusobacterium nucleatum-Induced MUC5AC Production in Human Airway Epithelial Cells

“…The NCI-H292 cells were plated in a 24-well plate, and MUC5AC protein was measured by performing ELISA as previously described (17)(18)(19)(20). After F. nucleatum Sup stimulation, the culture medium was collected as the cell supernatant.…”

“…The beneficial effects of macrolide therapy not only are related to its bactericidal properties but also extend to its immune-modulating and anti-inflammatory effects (16). We previously reported that macrolides inhibit MUC5AC production induced by several factors (Pseudomonas aeruginosa autoinducer [17], lipopolysaccharide [18], nontypeable Haemophilus influenzae [19], and Chlamydophila pneumoniae [20]) in human lung epithelial cells and found that mucin reduction by macrolides is related to several intracellular signal transduction, including extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation (17,18), NF-B activation (17,20), or AP-1 activation (19). As macrolides have no bactericidal activities against F. nucleatum, the effect of macrolides on mucin production compared with that of CLDM and MTZ would provide insight concerning the treatment of F. nucleatum respiratory tract infections.…”