Suppression of matrix metalloproteinase-9 production from neutrophils by a macrolide antibiotic, roxithromycin, in vitro

Mediators Inflamm. 2004 Dec;13(5-6):313-9. doi: 10.1080/09629350400008810.


Background: Macrolide antibiotics such as erythromycin and roxithromycin (RXM) have an anti-inflammatory effect that may account for their clinical benefit in the treatment of chronic airway inflammatory diseases. However, the precise mechanism of this anti-inflammatory effect is not well understood.

Purpose: The influence of RXM on matrix metalloproteinase (MMP)-9 production from neutrophils in response to lipopolysaccharide (LPS) stimulation was examined in vitro.

Methods: Neutrophils prepared from normal human peripheral blood (1 x 10(5) cells/ml) were treated with various concentrations of RXM for 1 h, and then stimulated with 1.0 microg/ml of LPS in the presence of the agent for 24 h. MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 levels in culture supernatants were examined by enzyme-linked immunosorbent assay.

Results: Addition of RXM at more than 5.0 microg/ml into cell cultures caused significant suppression of MMP-9 production, which was increased by LPS stimulation. However, the ability of cells to produce TIMP-1 was not affected by RXM treatment, even when the cells were cultured in the presence of agent at 10.0 microg/mL We then examined the influence of RXM on transcriptional factor, nuclear factor-kappaB and activator protein (AP)-1 activation by LPS stimulation. RXM exerted suppressive action on NF-kappaB (P50 and P65) activation when the cells were cultured for 4 h at more than 5.0 microg/ml of the agent. RXM at more than 2.5 microg/ml also suppressed AP-1 (Fra 1 and Jun B) activation in 4-h cultured cells. We finally examined the influence of RXM on MMP-9 mRNA expression in neutrophils. Addition of RXM into cell cultures at more than 5.0 microg/ml caused significant inhibition of mRNA expression, which was enhanced by LPS stimulation for 12 h.

Conclusion: These results strongly suggest that RXM inhibits neutrophil transmigration into inflammatory sites and results in favorable modification of the clinical status of inflammatory diseases.

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Cell Movement / drug effects
  • Gene Expression / drug effects
  • Humans
  • In Vitro Techniques
  • Inflammation / drug therapy
  • Inflammation / etiology
  • Inflammation / prevention & control
  • Lipopolysaccharides / pharmacology
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase Inhibitors*
  • NF-kappa B / antagonists & inhibitors
  • Neutrophils / drug effects*
  • Neutrophils / enzymology*
  • Neutrophils / physiology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Roxithromycin / pharmacology*
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
  • Transcription Factor AP-1 / antagonists & inhibitors


  • Anti-Bacterial Agents
  • Lipopolysaccharides
  • Matrix Metalloproteinase Inhibitors
  • NF-kappa B
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Transcription Factor AP-1
  • Roxithromycin
  • Matrix Metalloproteinase 9