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Roxithromycin inhibits tumor necrosis factor-alpha-induced matrix metalloproteinase-1 expression through regulating mitogen-activated protein kinase phosphorylation and Ets-1 expression.
J Periodontal Res. 2007 Feb; 42(1):53-61.JP

Abstract

BACKGROUND AND OBJECTIVE

In periodontitis, matrix metalloproteinases (MMPs) are upregulated in response to locally released inflammatory cytokines, resulting in pathologic processes. Roxithromycin is a 14-membered ring macrolide antibiotic with broad-spectrum antibacterial effects against oral pathogens and immunomodulatory effects. Recently, we reported that roxithromycin inhibits tumor necrosis factor (TNF)-alpha-induced vascular endothelial growth factor expression in human periodontal ligament (HPDL) cell cultures. In the present study, we examined the effect of roxithromycin on TNF-alpha-induced MMP-1 production by HPDL cells.

MATERIAL AND METHODS

Cultured cells were incubated with 1% fetal bovine serum for 24 h, followed by treatment with 10 ng/ml TNF-alpha, 10 microM roxithromycin, and mitogen-activated protein kinase inhibitor at various concentrations. Culture supernatants and sediments were collected at different time-points and used for enzyme-linked immunosorbent assays, and northern and western blot analyses.

RESULTS

In HPDL cell cultures, roxithromycin strongly inhibited TNF-alpha-induced MMP-1 mRNA expression and production. The inhibition of MMP-1 gene expression by roxithromycin was dependent on de novo protein synthesis and was regulated at the transcriptional level. Roxithromycin significantly inhibited TNF-alpha-induced c-Jun N-terminal kinase activation (JNP) and marginally inhibited extracellular signal-regulated kinase (ERK) 1/2 activation, but not p38 mitogen-activated protein kinase activation. Furthermore, roxithromycin reduced the induction of Ets-1, one of the critical factors in MMP-1 transcription.

CONCLUSION

Roxithromycin inhibits TNF-alpha-mediated MMP-1 induction through the downregulation of ERK1/2 and JNK activation and the subsequent reduction of Ets-1, suggesting that roxithromycin may have therapeutic use in periodontitis and other chronic inflammatory conditions involving MMP-1 induction.

Authors+Show Affiliations

Department of Restorative Dentistry and Endodontology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. oyatohru@dentc.hal.kagoshima-u.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17214640

Citation

Oyama, T, et al. "Roxithromycin Inhibits Tumor Necrosis Factor-alpha-induced Matrix Metalloproteinase-1 Expression Through Regulating Mitogen-activated Protein Kinase Phosphorylation and Ets-1 Expression." Journal of Periodontal Research, vol. 42, no. 1, 2007, pp. 53-61.
Oyama T, Matsushita K, Sakuta T, et al. Roxithromycin inhibits tumor necrosis factor-alpha-induced matrix metalloproteinase-1 expression through regulating mitogen-activated protein kinase phosphorylation and Ets-1 expression. J Periodontal Res. 2007;42(1):53-61.
Oyama, T., Matsushita, K., Sakuta, T., Tokuda, M., Tatsuyama, S., Nagaoka, S., & Torii, M. (2007). Roxithromycin inhibits tumor necrosis factor-alpha-induced matrix metalloproteinase-1 expression through regulating mitogen-activated protein kinase phosphorylation and Ets-1 expression. Journal of Periodontal Research, 42(1), 53-61.
Oyama T, et al. Roxithromycin Inhibits Tumor Necrosis Factor-alpha-induced Matrix Metalloproteinase-1 Expression Through Regulating Mitogen-activated Protein Kinase Phosphorylation and Ets-1 Expression. J Periodontal Res. 2007;42(1):53-61. PubMed PMID: 17214640.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Roxithromycin inhibits tumor necrosis factor-alpha-induced matrix metalloproteinase-1 expression through regulating mitogen-activated protein kinase phosphorylation and Ets-1 expression. AU - Oyama,T, AU - Matsushita,K, AU - Sakuta,T, AU - Tokuda,M, AU - Tatsuyama,S, AU - Nagaoka,S, AU - Torii,M, PY - 2007/1/12/pubmed PY - 2007/3/21/medline PY - 2007/1/12/entrez SP - 53 EP - 61 JF - Journal of periodontal research JO - J Periodontal Res VL - 42 IS - 1 N2 - BACKGROUND AND OBJECTIVE: In periodontitis, matrix metalloproteinases (MMPs) are upregulated in response to locally released inflammatory cytokines, resulting in pathologic processes. Roxithromycin is a 14-membered ring macrolide antibiotic with broad-spectrum antibacterial effects against oral pathogens and immunomodulatory effects. Recently, we reported that roxithromycin inhibits tumor necrosis factor (TNF)-alpha-induced vascular endothelial growth factor expression in human periodontal ligament (HPDL) cell cultures. In the present study, we examined the effect of roxithromycin on TNF-alpha-induced MMP-1 production by HPDL cells. MATERIAL AND METHODS: Cultured cells were incubated with 1% fetal bovine serum for 24 h, followed by treatment with 10 ng/ml TNF-alpha, 10 microM roxithromycin, and mitogen-activated protein kinase inhibitor at various concentrations. Culture supernatants and sediments were collected at different time-points and used for enzyme-linked immunosorbent assays, and northern and western blot analyses. RESULTS: In HPDL cell cultures, roxithromycin strongly inhibited TNF-alpha-induced MMP-1 mRNA expression and production. The inhibition of MMP-1 gene expression by roxithromycin was dependent on de novo protein synthesis and was regulated at the transcriptional level. Roxithromycin significantly inhibited TNF-alpha-induced c-Jun N-terminal kinase activation (JNP) and marginally inhibited extracellular signal-regulated kinase (ERK) 1/2 activation, but not p38 mitogen-activated protein kinase activation. Furthermore, roxithromycin reduced the induction of Ets-1, one of the critical factors in MMP-1 transcription. CONCLUSION: Roxithromycin inhibits TNF-alpha-mediated MMP-1 induction through the downregulation of ERK1/2 and JNK activation and the subsequent reduction of Ets-1, suggesting that roxithromycin may have therapeutic use in periodontitis and other chronic inflammatory conditions involving MMP-1 induction. SN - 0022-3484 UR - https://www.unboundmedicine.com/medline/citation/17214640/Roxithromycin_inhibits_tumor_necrosis_factor_alpha_induced_matrix_metalloproteinase_1_expression_through_regulating_mitogen_activated_protein_kinase_phosphorylation_and_Ets_1_expression_ L2 - https://doi.org/10.1111/j.1600-0765.2006.00914.x DB - PRIME DP - Unbound Medicine ER -