Macrolide antibiotics like azithromycin increase lipopolysaccharide-induced IL-8 production by human gingival fibroblasts

European Journal of Medical Research

P-L Wang²  Y Imamura²  Y Fujinami²  T Hattori²  T Ara²  A Kamemoto¹ 

[1] Department of Hard Tissue Research, Graduate School of Oral Medicine, Matsumoto Dental University;Department of Pharmacology, Matsumoto Dental University, Hirooka, Shiojiri, Nagano, Japan

关键词: anti-inflammatory effect;    interleukin-8;    human gingival fibroblast;    azithromycin;    macrolide antibiotics;   

Others  :  1093656
DOI  :  10.1186/2047-783X-14-7-309

 received in 2009-04-24, accepted in 2009-06-05,  发布年份 2009

【 摘 要 】

Objective

Macrolide antibiotics are reported to modulate the production of cytokines in various type of cells. We examined the effect of macrolide antibiotics on inflammatory cytokines (IL-6 and IL-8) and chemical mediator (PGE₂) and also matrix metalloproteinases (MMPs) productions by human gingival fibroblasts (HGFs) treated with lipopolysaccharide (LPS).

Methods

The effect of macrolide antibiotics [erythromycin (EM), azithromycin (AZM) and josamycin (JOM)] on HGFs proliferation were examined by MTT assay. HGFs were treated with LPS from Porphyromonas gingivalis (PgLPS) and macrolide antibiotics, and IL-6, IL-8 and PGE₂ levels were evaluated by ELISA. MMPs were detected by gelatin zymography.

Results

AZM slightly but significantly decreased HGFs proliferation, while EM and JOM did not affected. AZM increased PgLPS-induced IL-8 production dose-dependently, while AZM did not alter IL-6 and PGE₂ productions. EM and JOM did not altered PgLPS-induced IL-6, IL-8 and PGE₂ productions. All macrolide antibiotics did not alter MMPs production. These results indicate that macrolide antibiotics have no direct anti-inflammatory effect. However, the use of the inhibitors of cell signaling pathway failed to reveal the mechanism that AZM enhanced PgLPS-induced IL-8 production.

Conclusion

These results suggest macrolide antibiotics have an indirect anti-inflammatory effect as a result of their antimicrobial properties. Because AZM increased LPS-induced IL-8 production by HGFs, the possibility is considered that neutrophils may be migrated to periodontal tissue and phagocytize the periodontopathic bacteria more efficiently.

【 授权许可】

   
2009 I. Holzapfel Publishers

【 图 表 】

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【 参考文献 】

• [1]Costerton JW, Stewart PS, Greenberg EP: Bacterial biofilms: a common cause of persistent infections. Science 1999, 284:1318-1322.
• [2]Girard AE, Girard D, English AR, Gootz TD, Cimochowski CR, Faiella JA, Haskell SL, Retsema JA: Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother 1987, 31:1948-1954.
• [3]Baldwin DR, Wise R, Andrews JM, Ashby JP, Honey-bourne D: Azithromycin concentrations at the sites of pulmonary infection. Eur Respir J 1990, 3:886-890.
• [4]Davila D, Kolacny-Babic L, Plavsic F: Pharmacokinetics of azithromycin after single oral dosing of experimental animals. Biopharm Drug Dispos 1991, 12:505-514.
• [5]Blandizzi C, Malizia T, Lupetti A, Pesce D, Gabriele M, Giuca MR, Campa M, Del Tacca M, Senesi S: Periodontal tissue disposition of azithromycin in patients affected by chronic inflammatory periodontal diseases. J Periodontol 1999, 70:960-966.
• [6]Tateda K, Comte R, Pechere JC, Kohler T, Yamaguchi K, Van Delden C: Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2001, 45:1930-1933.
• [7]Tamura A, Ara T, Imamura Y, Fujii T, Wang PL: The effects of antibiotics on in vitro biofilm model of periodontal disease. Eur J Med Res 2008, 13:439-445.
• [8]Fujii T, Wang PL, Hosokawa Y, Shirai S, Tamura A, Hikita K, Maida T, Ochi M, Baehni PC: Effect of systemically administrated azithromcycin in early onset aggressive periodontitis. Perio 2004, 1:321-325.
• [9]Smith SR, Foyle DM, Daniels J, Joyston-Bechal S, Smales FC, Sefton A, Williams J: A double-blind placebo-controlled trial of azithromycin as an adjunct to non-surgical treatment of periodontitis in adults: clinical results. J Clin Periodontol 2002, 29:54-61.
• [10]Mascarenhas P, Gapski R, Al-Shammari K, Hill R, Soehren S, Fenno JC, Giannobile WV, Wang HL: Clinical response of azithromycin as an adjunct to nonsurgical periodontal therapy in smokers. J Periodontol 2005, 76:426-436.
• [11]Gomi K, Yashima A, Nagano T, Kanazashi M, Maeda N, Arai T: Effects of full-mouth scaling and root planing in conjunction with systemically administered azithromycin. J Periodontol 2007, 78:422-429.
• [12]Haas AN, de Castro GD, Moreno T, Susin C, Albandar JM, Oppermann RV, Rösing CK: Azithromycin as an adjunctive treatment of aggressive periodontitis: 12-months randomized clinical trial. J Clin Periodontol 2008, 35:696-704.
• [13]Kurdowska A, Noble JM, Griffith DE: The effect of azithromycin and clarithromycin on ex vivo interleukin-8 (IL-8) release from whole blood and IL-8 production by human alveolar macrophages. J Antimicrob Chemother 2001, 47:867-870.
• [14]Shinkai M, Foster GH, Rubin BK: Macrolide antibiotics modulate ERK phosphorylation and IL-8 and GMCSF production by human bronchial epithelial cells. Am J Physiol Lung Cell Mol Physiol 2006, 290:L75-85.
• [15]Uriarte SM, Molestina RE, Miller RD, Bernabo J, Farinati A, Eiguchi K, Ramirez JA, Summersgill JT: Effect of macrolide antibiotics on human endothelial cells activated by Chlamydia pneumoniae infection and tumor necrosis factor-a. J Infect Dis 2002, 185:1631-1636.
• [16]Cigana C, Nicolis E, Pasetto M, Assael BM, Melotti P: Anti-inflammatory effects of azithromycin in cystic fibrosis airway epithelial cells. Biochem Biophys Res Commun 2006, 350:977-982.
• [17]Cigana C, Assael BM, Melotti P: Azithromycin selectively reduces tumor necrosis factor alpha levels in cystic fibrosis airway epithelial cells. Antimicrob Agents Chemother 2007, 51:975-981.
• [18]Vanaudenaerde BM, Wuyts WA, Geudens N, Dupont LJ, Schoofs K, Smeets S, Van Raemdonck DE, Verleden GM: Macrolides inhibit IL17-induced IL8 and 8-isoprostane release from human airway smooth muscle cells. Am J Transplant 2007, 7:76-82.
• [19]Ivetic Tkalcevic V, Bosnjak B, Hrvacic B, Bosnar M, Marjanovic N, Ferencic Z, Situm K, Culic O, Parnham MJ, Erakovic V: Anti-inflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice. Eur J Pharmacol 2006, 539:131-138.
• [20]Bartold PM, Haynes DR: Interleukin-6 production by human gingival fibroblasts. J Periodontal Res 1991, 26:339-345.
• [21]Tamura M, Tokuda M, Nagaoka S, Takada H: Lipopolysaccharides of Bacteroides intermedius (Prevotella intermedia) and Bacteroides (Porphyromonas) gingivalis induce interleukin-8 gene expression in human gingival fibroblast cultures. Infect Immun 1992, 60:4932-4937.
• [22]Sismey-Durrant HJ, Hopps RM: Effect of lipopolysaccharide from Porphyromonas gingivalis on prostaglandin E2 and interleukin-1b release from rat periosteal and human gingival fibroblasts in vitro. Oral Microbiol Immunol 1991, 6:378-380.
• [23]Wang PL, Ohura K: Porphyromonas gingivalis lipopolysaccharide signaling in gingival fibroblasts-CD14 and Toll-like receptors. Crit Rev Oral Biol Med 2002, 13:132-142.
• [24]Ara T, Kurata K, Hirai K, Uchihashi T, Uematsu T, Imamura Y, Furusawa K, Kurihara S, Wang PL: Human gingival fibroblasts are critical in sustaining inflammation in periodontal disease. J Periodontal Res 2009, 44:21-27.
• [25]Ara T, Fujinami Y, Imamura Y, Wang PL: Lipopolysaccharide-treated human gingival fibroblasts continuously produce PGE2. J Hard Tissue Biol 2008, 17:121-124.
• [26]Wang PL, Sato K, Oido M, Fujii T, Kowashi Y, Shinohara M, Ohura K, Tani H, Kuboki Y: Involvement of CD14 on human gingival fibroblasts in Porphyromonas gingivalis lipopolysaccharide-mediated interleukin-6 secretion. Arch Oral Biol 1998, 43:687-694.
• [27]Heussen C, Dowdle EB: Electrophoretic analysis of plasminogen activators in polyacrylamide gels containing sodium dodecyl sulfate and copolymerized substrates. Anal Biochem 1980, 102:196-202.
• [28]Kurata K, Ara T, Kurihara S, Yamada K, Wang PL: LPS-stimulated Apert syndrome gingival keratinocytes show markedly suppressed inflammatory cytokine production. J Oral Biosci 2008, 50:59-67.
• [29]R Development Core Team R: A language and environment for statistical computing. R Foundation for Statistical Computing 2008.
• [30]Gomi K, Yashima A, Iino F, Kanazashi M, Nagano T, Shibukawa N, Ohshima T, Maeda N, Arai T: Drug concentration in inflamed periodontal tissues after systemically administered azithromycin. J Periodontol 2007, 78:918-923.
• [31]Takada H, Mihara J, Morisaki I, Hamada S: Induction of interleukin-1 and -6 in human gingival fibroblast cultures stimulated with Bacteroides lipopolysaccharides. Infect Immun 1991, 59:295-301.
• [32]Okada H, Murakami S: Cytokine expression in periodontal health and disease. Crit Rev Oral Biol Med 1998, 9:248-266.
• [33]Noguchi K, Ishikawa I: The roles of cyclooxygenase-2 and prostaglandin E2 in periodontal disease. Periodontol 2000 2007, 43:85-101.
• [34]Bouwman JJ, Visseren FL, Bouter PK, Diepersloot RJ: Azithromycin inhibits interleukin-6 but not fibrinogen production in hepatocytes infected with cytomegalovirus and Chlamydia pneumoniae. J Lab Clin Med 2004, 144:18-26.