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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Anti-Inflammatory Activity of Macrolide Antibiotics

Angela Ianaro, Armando Ialenti, Pasquale Maffia, Lidia Sautebin, Laura Rombolà, Rosa Carnuccio, Teresa Iuvone, Fulvio D'Acquisto and Massimo Di Rosa
Journal of Pharmacology and Experimental Therapeutics January 2000, 292 (1) 156-163;
Angela Ianaro
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Armando Ialenti
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Pasquale Maffia
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Lidia Sautebin
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Laura Rombolà
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Rosa Carnuccio
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Teresa Iuvone
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Fulvio D'Acquisto
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Massimo Di Rosa
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Abstract

The effect of four macrolide antibiotics (roxithromycin, clarithromycin, erythromycin, and azithromycin) on the generation of some mediators and cytokines involved in the inflammatory process has been studied both in vivo and in vitro. Rat carrageenin pleurisy was used as a model of acute inflammation, and the macrolides were administered (10, 20, and 40 mg/kg p.o.) 1 h before the carrageenin challenge. Exudate volume and leukocyte accumulation were both dose-dependently reduced by roxithromycin, clarithromycin and erythromycin in either normal or adrenalectomized animals. Furthermore, in normal rats, prostaglandin (PG)E2, nitrate plus nitrite, and tumor necrosis factor-α levels in pleural exudate were significantly reduced by these macrolides. Roxithromycin appeared more effective than erythromycin and clarithromycin, whereas azithromycin only slightly affected the inflammatory reaction. None of the macrolides were able to modify leukotriene B4 exudate levels. In vitro experiments have shown that the four macrolides (5–80 μM) reduced in a concentration-dependent manner the production of 6-keto-PGF1α, NO2−, tumor necrosis factor-α, interleukin-1β, and interleukin-6 by lipopolysaccharide-stimulated J774 macrophages. In J774 cells, the inhibition of 6-keto-PGF1α and NO2− production by roxithromycin and erythromycin was not dependent on direct inhibition of cyclooxygenase-2 and inducible nitric oxide synthase activity because it appears to be related to the inhibition of cyclooxygenase-2 and inducible nitric oxide synthase protein expression. In conclusion, the present study shows that macrolide antibiotics have anti-inflammatory activity, which likely depends on their ability to prevent the production of proinflammatory mediators and cytokines, and suggest that these agents, particularly roxithromycin, can exert therapeutic effects independently of their antibacterial activity.

Footnotes

  • Send reprint requests to: Prof. Massimo Di Rosa, Department of Experimental Pharmacology, University of Naples “Federico II,” Via D. Montesano, 49, 80131, Naples, Italy. E-mail: dirosa{at}unina.it

  • Abbreviations:
    LPS
    lipopolysaccharide
    LTB4
    leukotriene B4
    PGE2
    prostaglandin E2
    ELISA
    enzyme-linked immunosorbent assay
    6-keto-PGF1α
    6-keto-prostaglandin F1α
    COX-2
    cyclooxygenase-2
    NO
    nitric oxide
    iNOS
    inducible nitric oxide synthase
    IL-1β
    interleukin-1β
    IL-6
    interleukin-6
    NF-κB
    nuclear factor-κB
    TNF-α
    tumor necrosis factor-α
    NO3−
    nitrate
    NO2−
    nitrite
    NOx
    nitrate plus nitrite
    l-NMMA
    NG-monomethyl-l-arginine
    • Received May 10, 1999.
    • Accepted September 6, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 1
1 Jan 2000
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Anti-Inflammatory Activity of Macrolide Antibiotics

Angela Ianaro, Armando Ialenti, Pasquale Maffia, Lidia Sautebin, Laura Rombolà, Rosa Carnuccio, Teresa Iuvone, Fulvio D'Acquisto and Massimo Di Rosa
Journal of Pharmacology and Experimental Therapeutics January 1, 2000, 292 (1) 156-163;

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

Anti-Inflammatory Activity of Macrolide Antibiotics

Angela Ianaro, Armando Ialenti, Pasquale Maffia, Lidia Sautebin, Laura Rombolà, Rosa Carnuccio, Teresa Iuvone, Fulvio D'Acquisto and Massimo Di Rosa
Journal of Pharmacology and Experimental Therapeutics January 1, 2000, 292 (1) 156-163;
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