Anti-inflammatory activity of macrolide antibiotics.
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)E(2), nitrate plus nitrite, and tumor necrosis factor-alpha 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 B(4) exudate levels. In vitro experiments have shown that the four macrolides (5-80 microM) reduced in a concentration-dependent manner the production of 6-keto-PGF(1alpha), NO(2)(-), tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 by lipopolysaccharide-stimulated J774 macrophages. In J774 cells, the inhibition of 6-keto-PGF(1alpha) and NO(2)(-) 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.
Ianaro
A
A
Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.
Ialenti
A
A
Maffia
P
P
Sautebin
L
L
Rombolà
L
L
Carnuccio
R
R
Iuvone
T
T
D'Acquisto
F
F
Di Rosa
M
M
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000315:Adrenalectomy; D000758:Anesthesia; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology; D002351:Carrageenan; D002460:Cell Line; D017291:Clarithromycin / Q000494:pharmacology; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004917:Erythromycin / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010998:Pleurisy / Q000139:chemically induced / Q000517:prevention & control; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D015575:Roxithromycin / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D007527:Isoenzymes; D009566:Nitrates; D009573:Nitrites; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D015575:Roxithromycin; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D004917:Erythromycin; D017963:Azithromycin; D002351:Carrageenan; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D017291:Clarithromycin; D015232:Dinoprostone