Clarithromycin has an immunomodulatory effect on ERK-mediated inflammation induced by Pseudomonas aeruginosa flagellin

J Antimicrob Chemother. 2007 Jun;59(6):1096-101. doi: 10.1093/jac/dkm084. Epub 2007 Apr 5.


Objectives: Pseudomonas aeruginosa exoproducts are potent triggers of immune responses in eukaryotic cells. Clarithromycin initially decreases, then increases and finally produces a sustained suppression of interleukin (IL)-8 secretion from normal human bronchial epithelial (NHBE) cells through inhibition and activation of extracellular signal-regulated kinase (ERK). This polyphasic immune response is referred to as immunomodulation.

Methods: We studied the effects of P. aeruginosa flagellin and alginate on IL-8 secretion from NHBE cells and how this was affected by clarithromycin or dexamethasone. We also assessed the upstream kinase cell signalling intermediates that appear to be responsible for flagellin-induced IL-8 secretion. ELISA was used to measure IL-8 in culture supernatants, and western blots were used to measure kinase and phosphokinase levels.

Results: Flagellin dose-dependently increased IL-8 secretion in NHBE cells at 24 h, whereas alginate had no effect on IL-8. Clarithromycin significantly decreased flagellin-induced IL-8 over the first 9 h but not at 24 h. A 60 min exposure to clarithromycin decreased flagellin-induced ERK phosphorylation, but at 24 h, clarithromycin increased phospho-ERK1/2 beyond the effect of flagellin alone. Pre-treatment with PD98059 (MEK inhibitor) decreased flagellin-induced IL-8 secretion by 47.7% (P < 0.0001) compared with control flagellin exposure and decreased basal IL-8 in the absence of flagellin by 27.9% compared with untreated control cells (P < 0.0001). Dexamethasone and PD98059 together had an additive suppressive effect on flagellin-induced IL-8 secretion.

Conclusions: P. aeruginosa flagellin, but not alginate, stimulates IL-8 secretion in NHBE cells in part through ERK1/2. This effect is modulated by clarithromycin, whereas suppression of IL-8 secretion by dexamethasone probably occurs through different pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alginates / pharmacology
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Inflammatory Agents / pharmacology
  • Clarithromycin / pharmacology*
  • Dexamethasone / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / physiology*
  • Flagellin* / isolation & purification
  • Immunologic Factors*
  • Indicators and Reagents
  • Inflammation / chemically induced*
  • Inflammation / enzymology
  • Inflammation / pathology*
  • Interleukin-8 / metabolism
  • Lipopolysaccharides / pharmacology
  • Phosphorylation
  • Pseudomonas aeruginosa / chemistry*
  • Signal Transduction / drug effects
  • p38 Mitogen-Activated Protein Kinases / genetics


  • Alginates
  • Anti-Bacterial Agents
  • Anti-Inflammatory Agents
  • Immunologic Factors
  • Indicators and Reagents
  • Interleukin-8
  • Lipopolysaccharides
  • Flagellin
  • Dexamethasone
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Clarithromycin