Skip to main content
Erschienen in: Clinical Oral Investigations 2/2015

01.03.2015 | Original Article

Azithromycin suppresses P. gingivalis LPS-induced pro-inflammatory cytokine and chemokine production by human gingival fibroblasts in vitro

verfasst von: C. J. Doyle, T. R. Fitzsimmons, C. Marchant, A. A. S. S. K. Dharmapatni, R. Hirsch, P. M. Bartold

Erschienen in: Clinical Oral Investigations | Ausgabe 2/2015

Einloggen, um Zugang zu erhalten

Abstract

Objective

Azithromycin is a macrolide antibiotic that appears to have both antibacterial and anti-inflammatory properties. This study aimed to investigate the effect of azithromycin on the production of pro-inflammatory cytokines and chemokines by human gingival fibroblasts (HGF) in vitro.

Materials and methods

The effects of azithromycin (0.1 to 10 μg/mL) on the production of interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein 1 (MCP-1), and growth-regulated oncogene (GRO) by human gingival fibroblasts cultured in the presence or absence of Porphyromonas gingivalis lipopolysaccharide (LPS) was studied. Cytokine and chemokine protein levels in the culture supernatant were assessed using a Luminex® multiplex immunoassay.

Results

P. gingivalis LPS induced cytokine/chemokine (IL-6, IL-8, MCP-1, and GRO) protein production in HGFs, and this effect was suppressed by azithromycin at all concentrations tested.

Conclusions

This study demonstrates that azithromycin suppresses P. gingivalis LPS-induced cytokine/chemokine protein production in HGF, which may explain some of the clinical benefits observed with the adjunctive use of azithromycin in the treatment of periodontitis.

Clinical relevance

The current study examines the anti-inflammatory properties of azithromycin which may make it useful as an adjunct treatment to periodontitis. Specifically, we used azithromycin to modulate the production of pro-inflammatory cytokines by gingival fibroblasts known to be important in periodontal inflammation.
Literatur
1.
Zurück zum Zitat Di Benedetto A, Gigante I, Colucci S, Grano M (2013) Periodontal disease: linking the primary inflammation to bone loss. Clin Dev Immunol 2013:503754CrossRefPubMedCentralPubMed Di Benedetto A, Gigante I, Colucci S, Grano M (2013) Periodontal disease: linking the primary inflammation to bone loss. Clin Dev Immunol 2013:503754CrossRefPubMedCentralPubMed
2.
Zurück zum Zitat Greenstein G (1992) Periodontal response to mechanical non-surgical therapy: a review. J Periodontol 63:118–130CrossRefPubMed Greenstein G (1992) Periodontal response to mechanical non-surgical therapy: a review. J Periodontol 63:118–130CrossRefPubMed
3.
Zurück zum Zitat Drisko CH (2001) Nonsurgical periodontal therapy. Periodontol 2000(25):77–88CrossRef Drisko CH (2001) Nonsurgical periodontal therapy. Periodontol 2000(25):77–88CrossRef
4.
Zurück zum Zitat Gomi K, Yashima A, Nagano T, Kanazashi M, Maeda N, Arai T (2007) Effects of full-mouth scaling and root planing in conjunction with systemically administered azithromycin. J Periodontol 78:422–429CrossRefPubMed Gomi K, Yashima A, Nagano T, Kanazashi M, Maeda N, Arai T (2007) Effects of full-mouth scaling and root planing in conjunction with systemically administered azithromycin. J Periodontol 78:422–429CrossRefPubMed
5.
Zurück zum Zitat Heitz-Mayfield LJ (2009) Systemic antibiotics in periodontal therapy. Aust Dent J 54(Suppl 1):S96–S101CrossRefPubMed Heitz-Mayfield LJ (2009) Systemic antibiotics in periodontal therapy. Aust Dent J 54(Suppl 1):S96–S101CrossRefPubMed
6.
Zurück zum Zitat Preshaw PM (2008) Host response modulation in periodontics. Periodontol 2000(48):92–110CrossRef Preshaw PM (2008) Host response modulation in periodontics. Periodontol 2000(48):92–110CrossRef
7.
Zurück zum Zitat Pajukanta R (1993) In vitro antimicrobial susceptibility of Porphyromonas gingivalis to azithromycin, a novel macrolide. Oral Microbiol Immunol 8:325–326CrossRefPubMed Pajukanta R (1993) In vitro antimicrobial susceptibility of Porphyromonas gingivalis to azithromycin, a novel macrolide. Oral Microbiol Immunol 8:325–326CrossRefPubMed
8.
Zurück zum Zitat Pajukanta R, Asikainen S, Saarela M, Alaluusua S, Jousimies-Somer H (1992) In vitro activity of azithromycin compared with that of erythromycin against Actinobacillus actinomycetemcomitans. Antimicrob Agents Chemother 36:1241–1243CrossRefPubMedCentralPubMed Pajukanta R, Asikainen S, Saarela M, Alaluusua S, Jousimies-Somer H (1992) In vitro activity of azithromycin compared with that of erythromycin against Actinobacillus actinomycetemcomitans. Antimicrob Agents Chemother 36:1241–1243CrossRefPubMedCentralPubMed
9.
Zurück zum Zitat Bartold PM, du Bois AH, Gannon S, Haynes DR, Hirsch RS (2013) Antibacterial and immunomodulatory properties of azithromycin treatment implications for periodontitis. Inflammopharmacology 21:321–338CrossRefPubMed Bartold PM, du Bois AH, Gannon S, Haynes DR, Hirsch RS (2013) Antibacterial and immunomodulatory properties of azithromycin treatment implications for periodontitis. Inflammopharmacology 21:321–338CrossRefPubMed
10.
Zurück zum Zitat Hirsch R, Deng H, Laohachai MN (2012) Azithromycin in periodontal treatment: more than an antibiotic. J Periodontal Res 47:137–148CrossRefPubMed Hirsch R, Deng H, Laohachai MN (2012) Azithromycin in periodontal treatment: more than an antibiotic. J Periodontal Res 47:137–148CrossRefPubMed
11.
Zurück zum Zitat Muniz FW, de Oliveira CC, de Sousa CR, Moreira MM, de Moraes ME, Martins RS (2013) Azithromycin: a new concept in adjuvant treatment of periodontitis. Eur J Pharmacol 705:135–139CrossRefPubMed Muniz FW, de Oliveira CC, de Sousa CR, Moreira MM, de Moraes ME, Martins RS (2013) Azithromycin: a new concept in adjuvant treatment of periodontitis. Eur J Pharmacol 705:135–139CrossRefPubMed
12.
Zurück zum Zitat Hirsch R (2010) Periodontal healing and bone regeneration in response to azithromycin. Aust Dent J 55:193–199CrossRefPubMed Hirsch R (2010) Periodontal healing and bone regeneration in response to azithromycin. Aust Dent J 55:193–199CrossRefPubMed
13.
Zurück zum Zitat Schmidt EF, Bretz WA (2007) Benefits of additional courses of systemic azithromycin in periodontal disease case report. N Y State Dent J 73:40–45PubMed Schmidt EF, Bretz WA (2007) Benefits of additional courses of systemic azithromycin in periodontal disease case report. N Y State Dent J 73:40–45PubMed
14.
Zurück zum Zitat Altenburg J, de Graaff CS, van der Werf TS, Boersma WG (2011) Immunomodulatory effects of macrolide antibiotics—part 1: biological mechanisms. Respir Int Rev Thorac Dis 81:67–74 Altenburg J, de Graaff CS, van der Werf TS, Boersma WG (2011) Immunomodulatory effects of macrolide antibiotics—part 1: biological mechanisms. Respir Int Rev Thorac Dis 81:67–74
15.
Zurück zum Zitat Kudoh S, Uetake T, Hagiwara K, Hirayama M, Hus LH, Kimura H, Sugiyama Y (1987) Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis. Nihon Kyobu Shikkan Gakkai Zasshi 25:632–642PubMed Kudoh S, Uetake T, Hagiwara K, Hirayama M, Hus LH, Kimura H, Sugiyama Y (1987) Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis. Nihon Kyobu Shikkan Gakkai Zasshi 25:632–642PubMed
16.
Zurück zum Zitat Bartold PM, Van Dyke TE (2013) Periodontitis: a host-mediated disruption of microbial homeostasis. Unlearning learned concepts. Periodontol 2000(62):203–217CrossRef Bartold PM, Van Dyke TE (2013) Periodontitis: a host-mediated disruption of microbial homeostasis. Unlearning learned concepts. Periodontol 2000(62):203–217CrossRef
17.
Zurück zum Zitat Kamemoto A, Ara T, Hattori T, Fujinami Y, Imamura Y, Wang PL (2009) Macrolide antibiotics like azithromycin increase lipopolysaccharide-induced IL-8 production by human gingival fibroblasts. Eur J Med Res 14:309–314CrossRefPubMedCentralPubMed Kamemoto A, Ara T, Hattori T, Fujinami Y, Imamura Y, Wang PL (2009) Macrolide antibiotics like azithromycin increase lipopolysaccharide-induced IL-8 production by human gingival fibroblasts. Eur J Med Res 14:309–314CrossRefPubMedCentralPubMed
18.
Zurück zum Zitat Gannon SC, Cantley MD, Haynes DR, Hirsch R, Bartold PM (2013) Azithromycin suppresses human osteoclast formation and activity in vitro. J Cell Physiol 228:1098–1107CrossRefPubMed Gannon SC, Cantley MD, Haynes DR, Hirsch R, Bartold PM (2013) Azithromycin suppresses human osteoclast formation and activity in vitro. J Cell Physiol 228:1098–1107CrossRefPubMed
19.
Zurück zum Zitat Takashiba S, Naruishi K, Murayama Y (2003) Perspective of cytokine regulation for periodontal treatment: fibroblast biology. J Periodontol 74:103–110CrossRefPubMed Takashiba S, Naruishi K, Murayama Y (2003) Perspective of cytokine regulation for periodontal treatment: fibroblast biology. J Periodontol 74:103–110CrossRefPubMed
20.
Zurück zum Zitat Scheres N, Laine ML, de Vries TJ, Everts V, van Winkelhoff AJ (2010) Gingival and periodontal ligament fibroblasts differ in their inflammatory response to viable Porphyromonas gingivalis. J Periodontal Res 45:262–270CrossRefPubMed Scheres N, Laine ML, de Vries TJ, Everts V, van Winkelhoff AJ (2010) Gingival and periodontal ligament fibroblasts differ in their inflammatory response to viable Porphyromonas gingivalis. J Periodontal Res 45:262–270CrossRefPubMed
21.
Zurück zum Zitat Morandini AC, Sipert CR, Gasparoto TH, Greghi SL, Passanezi E, Rezende ML, Sant’ana AP, Campanelli AP, Garlet GP, Santos CF (2010) Differential production of macrophage inflammatory protein-1alpha, stromal-derived factor-1, and IL-6 by human cultured periodontal ligament and gingival fibroblasts challenged with lipopolysaccharide from P. gingivalis. J Periodontol 81:310–317CrossRefPubMed Morandini AC, Sipert CR, Gasparoto TH, Greghi SL, Passanezi E, Rezende ML, Sant’ana AP, Campanelli AP, Garlet GP, Santos CF (2010) Differential production of macrophage inflammatory protein-1alpha, stromal-derived factor-1, and IL-6 by human cultured periodontal ligament and gingival fibroblasts challenged with lipopolysaccharide from P. gingivalis. J Periodontol 81:310–317CrossRefPubMed
22.
Zurück zum Zitat Ara T, Kurata K, Hirai K, Uchihashi T, Uematsu T, Imamura Y, Furusawa K, Kurihara S, Wang PL (2009) Human gingival fibroblasts are critical in sustaining inflammation in periodontal disease. J Periodontal Res 44:21–27CrossRefPubMed Ara T, Kurata K, Hirai K, Uchihashi T, Uematsu T, Imamura Y, Furusawa K, Kurihara S, Wang PL (2009) Human gingival fibroblasts are critical in sustaining inflammation in periodontal disease. J Periodontal Res 44:21–27CrossRefPubMed
23.
Zurück zum Zitat Jonsson D, Amisten S, Bratthall G, Holm A, Nilsson BO (2009) LPS induces GROalpha chemokine production via NF-kappaB in oral fibroblasts. Inflamm Res 58:791–796CrossRefPubMed Jonsson D, Amisten S, Bratthall G, Holm A, Nilsson BO (2009) LPS induces GROalpha chemokine production via NF-kappaB in oral fibroblasts. Inflamm Res 58:791–796CrossRefPubMed
24.
Zurück zum Zitat Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, Yamaguchi A, Yoshiki S, Matsuda T, Hirano T et al (1990) IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 145:3297–3303PubMed Ishimi Y, Miyaura C, Jin CH, Akatsu T, Abe E, Nakamura Y, Yamaguchi A, Yoshiki S, Matsuda T, Hirano T et al (1990) IL-6 is produced by osteoblasts and induces bone resorption. J Immunol 145:3297–3303PubMed
25.
Zurück zum Zitat Wada N, Maeda H, Yoshimine Y, Akamine A (2004) Lipopolysaccharide stimulates expression of osteoprotegerin and receptor activator of NF-kappa B ligand in periodontal ligament fibroblasts through the induction of interleukin-1 beta and tumor necrosis factor-alpha. Bone 35:629–635CrossRefPubMed Wada N, Maeda H, Yoshimine Y, Akamine A (2004) Lipopolysaccharide stimulates expression of osteoprotegerin and receptor activator of NF-kappa B ligand in periodontal ligament fibroblasts through the induction of interleukin-1 beta and tumor necrosis factor-alpha. Bone 35:629–635CrossRefPubMed
26.
Zurück zum Zitat Mogi M, Otogoto J, Ota N, Inagaki H, Minami M, Kojima K (1999) Interleukin 1 beta, interleukin 6, beta 2-microglobulin, and transforming growth factor-alpha in gingival crevicular fluid from human periodontal disease. Arch Oral Biol 44:535–539CrossRefPubMed Mogi M, Otogoto J, Ota N, Inagaki H, Minami M, Kojima K (1999) Interleukin 1 beta, interleukin 6, beta 2-microglobulin, and transforming growth factor-alpha in gingival crevicular fluid from human periodontal disease. Arch Oral Biol 44:535–539CrossRefPubMed
27.
Zurück zum Zitat Fitzsimmons TR, Sanders AE, Slade GD, Bartold PM (2009) Biomarkers of periodontal inflammation in the Australian adult population. Aust Dent J 54:115–122CrossRefPubMed Fitzsimmons TR, Sanders AE, Slade GD, Bartold PM (2009) Biomarkers of periodontal inflammation in the Australian adult population. Aust Dent J 54:115–122CrossRefPubMed
28.
Zurück zum Zitat Yu X, Graves DT (1995) Fibroblasts, mononuclear phagocytes, and endothelial cells express monocyte chemoattractant protein-1 (MCP-1) in inflamed human gingiva. J Periodontol 66:80–88CrossRefPubMed Yu X, Graves DT (1995) Fibroblasts, mononuclear phagocytes, and endothelial cells express monocyte chemoattractant protein-1 (MCP-1) in inflamed human gingiva. J Periodontol 66:80–88CrossRefPubMed
29.
Zurück zum Zitat Wang PL, Ohura K, Fujii T, Oido-Mori M, Kowashi Y, Kikuchi M, Suetsugu Y, Tanaka J (2003) DNA microarray analysis of human gingival fibroblasts from healthy and inflammatory gingival tissues. Biochem Biophys Res Commun 305:970–973CrossRefPubMed Wang PL, Ohura K, Fujii T, Oido-Mori M, Kowashi Y, Kikuchi M, Suetsugu Y, Tanaka J (2003) DNA microarray analysis of human gingival fibroblasts from healthy and inflammatory gingival tissues. Biochem Biophys Res Commun 305:970–973CrossRefPubMed
30.
Zurück zum Zitat Wada N, Wang B, Lin NH, Laslett AL, Gronthos S, Bartold PM (2011) Induced pluripotent stem cell lines derived from human gingival fibroblasts and periodontal ligament fibroblasts. J Periodontal Res 46:438–447CrossRefPubMed Wada N, Wang B, Lin NH, Laslett AL, Gronthos S, Bartold PM (2011) Induced pluripotent stem cell lines derived from human gingival fibroblasts and periodontal ligament fibroblasts. J Periodontal Res 46:438–447CrossRefPubMed
31.
Zurück zum Zitat Gomi K, Yashima A, Iino F, Kanazashi M, Nagano T, Shibukawa N, Ohshima T, Maeda N, Arai T (2007) Drug concentration in inflamed periodontal tissues after systemically administered azithromycin. J Periodontol 78:918–923CrossRefPubMed Gomi K, Yashima A, Iino F, Kanazashi M, Nagano T, Shibukawa N, Ohshima T, Maeda N, Arai T (2007) Drug concentration in inflamed periodontal tissues after systemically administered azithromycin. J Periodontol 78:918–923CrossRefPubMed
32.
Zurück zum Zitat Lai PC, Ho W, Jain N, Walters JD (2011) Azithromycin concentrations in blood and gingival crevicular fluid after systemic administration. J Periodontol 82:1582–1586CrossRefPubMedCentralPubMed Lai PC, Ho W, Jain N, Walters JD (2011) Azithromycin concentrations in blood and gingival crevicular fluid after systemic administration. J Periodontol 82:1582–1586CrossRefPubMedCentralPubMed
33.
Zurück zum Zitat Malizia T, Tejada MR, Ghelardi E, Senesi S, Gabriele M, Giuca MR, Blandizzi C, Danesi R, Campa M, Del Tacca M (1997) Periodontal tissue disposition of azithromycin. J Periodontol 68:1206–1209CrossRefPubMed Malizia T, Tejada MR, Ghelardi E, Senesi S, Gabriele M, Giuca MR, Blandizzi C, Danesi R, Campa M, Del Tacca M (1997) Periodontal tissue disposition of azithromycin. J Periodontol 68:1206–1209CrossRefPubMed
35.
Zurück zum Zitat Ho W, Eubank T, Leblebicioglu B, Marsh C, Walters J (2010) Azithromycin decreases crevicular fluid volume and mediator content. J Dent Res 89:831–835CrossRefPubMedCentralPubMed Ho W, Eubank T, Leblebicioglu B, Marsh C, Walters J (2010) Azithromycin decreases crevicular fluid volume and mediator content. J Dent Res 89:831–835CrossRefPubMedCentralPubMed
36.
Zurück zum Zitat Matsumura Y, Mitani A, Suga T, Kamiya Y, Kikuchi T, Tanaka S, Aino M, Noguchi T (2011) Azithromycin may inhibit interleukin-8 through suppression of Rac1 and a nuclear factor-kappa B pathway in KB cells stimulated with lipopolysaccharide. J Periodontol 82:1623–1631CrossRefPubMed Matsumura Y, Mitani A, Suga T, Kamiya Y, Kikuchi T, Tanaka S, Aino M, Noguchi T (2011) Azithromycin may inhibit interleukin-8 through suppression of Rac1 and a nuclear factor-kappa B pathway in KB cells stimulated with lipopolysaccharide. J Periodontol 82:1623–1631CrossRefPubMed
37.
Zurück zum Zitat Zhou J, Windsor LJ (2007) Heterogeneity in the collagen-degrading ability of Porphyromonas gingivalis-stimulated human gingival fibroblasts. J Periodontal Res 42:77–84CrossRefPubMed Zhou J, Windsor LJ (2007) Heterogeneity in the collagen-degrading ability of Porphyromonas gingivalis-stimulated human gingival fibroblasts. J Periodontal Res 42:77–84CrossRefPubMed
38.
Zurück zum Zitat Retsema J, Girard A, Schelkly W, Manousos M, Anderson M, Bright G, Borovoy R, Brennan L, Mason R (1987) Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against gram-negative organisms. Antimicrob Agents Chemother 31:1939–1947CrossRefPubMedCentralPubMed Retsema J, Girard A, Schelkly W, Manousos M, Anderson M, Bright G, Borovoy R, Brennan L, Mason R (1987) Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolide with improved potency against gram-negative organisms. Antimicrob Agents Chemother 31:1939–1947CrossRefPubMedCentralPubMed
39.
Zurück zum Zitat Bartold PM, Narayanan AS (2006) Molecular and cell biology of healthy and diseased periodontal tissues. Periodontol 2000(40):29–49CrossRef Bartold PM, Narayanan AS (2006) Molecular and cell biology of healthy and diseased periodontal tissues. Periodontol 2000(40):29–49CrossRef
Metadaten
Titel
Azithromycin suppresses P. gingivalis LPS-induced pro-inflammatory cytokine and chemokine production by human gingival fibroblasts in vitro
verfasst von
C. J. Doyle
T. R. Fitzsimmons
C. Marchant
A. A. S. S. K. Dharmapatni
R. Hirsch
P. M. Bartold
Publikationsdatum
01.03.2015
Verlag
Springer Berlin Heidelberg
Erschienen in
Clinical Oral Investigations / Ausgabe 2/2015
Print ISSN: 1432-6981
Elektronische ISSN: 1436-3771
DOI
https://doi.org/10.1007/s00784-014-1249-7

Weitere Artikel der Ausgabe 2/2015

Clinical Oral Investigations 2/2015 Zur Ausgabe

Parodontalbehandlung verbessert Prognose bei Katheterablation

19.04.2024 Vorhofflimmern Nachrichten

Werden Personen mit Vorhofflimmern in der Blanking-Periode nach einer Katheterablation gegen eine bestehende Parodontitis behandelt, verbessert dies die Erfolgsaussichten. Dafür sprechen die Resultate einer prospektiven Untersuchung.

Invasive Zahnbehandlung: Wann eine Antibiotikaprophylaxe vor infektiöser Endokarditis schützt

11.04.2024 Endokarditis Nachrichten

Bei welchen Personen eine Antibiotikaprophylaxe zur Prävention einer infektiösen Endokarditis nach invasiven zahnärztlichen Eingriffen sinnvoll ist, wird diskutiert. Neue Daten stehen im Einklang mit den europäischen Leitlinienempfehlungen.

Zell-Organisatoren unter Druck: Mechanismen des embryonalen Zahnwachstums aufgedeckt

08.04.2024 Zahnmedizin Nachrichten

Der Aufbau von Geweben und Organen während der Embryonalentwicklung wird von den Zellen bemerkenswert choreografiert. Für diesen Prozess braucht es spezielle sogenannte „Organisatoren“. In einer aktuellen Veröffentlichung im Fachjournal Nature Cell Biology berichten Forschende durch welchen Vorgang diese Organisatoren im Gewebe entstehen und wie sie dann die Bildung von Zähnen orchestrieren.

Die Oralprophylaxe & Kinderzahnheilkunde umbenannt

11.03.2024 Kinderzahnmedizin Nachrichten

Infolge der Umbenennung der Deutschen Gesellschaft für Kinderzahnheilkunde in Deutsche Gesellschaft für Kinderzahnmedizin (DGKiZ) wird deren Mitgliederzeitschrift Oralprophylaxe & Kinderzahnheilkunde in Oralprophylaxe & Kinderzahnmedizin umbenannt. Aus diesem Grunde trägt die erste Ausgabe in 2024 erstmalig den neuen Titel.

Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Zahnmedizin und bleiben Sie gut informiert – ganz bequem per eMail.