Clarithromycin inhibits interleukin-13-induced goblet cell hyperplasia in human airway cells

Am J Respir Cell Mol Biol. 2011 Nov;45(5):1075-83. doi: 10.1165/rcmb.2010-0327OC. Epub 2011 Jun 3.

Abstract

IL-13 is a T-helper class 2 cytokine that induces goblet cell hyperplasia and mucus production in airway epithelial cells. Because macrolide antibiotics are known to have immunomodulatory and mucoregulatory properties, the aim of this study was to examine the effect of clarithromycin on IL-13-induced goblet cell hyperplasia and mucin hypersecretion in normal human bronchial epithelial (NHBE) cells. NHBE cells were cultured to differentiation at an air-liquid interface with IL-13 plus clarithromycin or vehicle. Histochemical analysis was performed using H&E staining, periodic acid-Schiff (PAS) staining, and MUC5AC immunostaining. MUC5AC synthesis was assayed using RT-PCR and ELISA. Western blotting was used to evaluate signaling pathways. IL-13 significantly increased the number of PAS-positive, MUC5AC-positive goblet cells, and this was significantly attenuated by clarithromycin at concentrations greater than 8 μg/ml (P < 0.01). Clarithromycin also dose-dependently decreased MUC5AC mRNA expression induced by IL-13 (P < 0.001), and, at 24 μg/ml, clarithromycin significantly attenuated the amount of MUC5AC protein in cell supernatants (P < 0.01). Western blotting showed that clarithromycin affected IL-13 receptor janus kinase signal transducers, activators of transcription6 (STAT6), and epidermal growth factor receptor mitogen-activated protein kinase signaling and that inhibition of these pathways by clarithromycin decreased goblet cell hyperplasia via nuclear factor-κB inactivation. We conclude that clarithromycin inhibits goblet cell hyperplasia and may directly regulate mucus secretion by IL-13 in NHBE cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bronchi / drug effects*
  • Bronchi / metabolism
  • Bronchi / pathology
  • Cell Differentiation / drug effects
  • Clarithromycin / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • ErbB Receptors / metabolism
  • Flavonoids / pharmacology
  • Goblet Cells / drug effects*
  • Goblet Cells / metabolism
  • Goblet Cells / pathology
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Hyperplasia / drug therapy
  • Hyperplasia / metabolism
  • Hyperplasia / pathology
  • Interleukin-13 / antagonists & inhibitors*
  • Isoxazoles / pharmacology
  • Janus Kinases / metabolism
  • Leflunomide
  • MAP Kinase Signaling System / drug effects
  • Mucin 5AC / metabolism
  • Mucus / drug effects
  • Mucus / metabolism
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Protein Synthesis Inhibitors / pharmacology*
  • Pyridines / pharmacology
  • Respiratory Mucosa / drug effects*
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • STAT6 Transcription Factor / metabolism
  • Signal Transduction / drug effects

Substances

  • Enzyme Inhibitors
  • Flavonoids
  • Heterocyclic Compounds, 3-Ring
  • Interleukin-13
  • Isoxazoles
  • MUC5AC protein, human
  • Mucin 5AC
  • NF-kappa B
  • PS1145
  • Protein Synthesis Inhibitors
  • Pyridines
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • EGFR protein, human
  • ErbB Receptors
  • Janus Kinases
  • Leflunomide
  • Clarithromycin
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one