Roxithromycin inhibits tumor necrosis factor-α-induced matrix metalloproteinase-1 expression through regulating mitogen-activated protein kinase phosphorylation and Ets-1 expression
Roxithromycin inhibits tumor necrosis factor-α-induced matrix metalloproteinase-1 expression through regulating mitogen-activated protein kinase phosphorylation and Ets-1 expression
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DOI：
10.1111/j.1600-0765.2006.00914.x
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发表时间：
2007-02-01
影响因子：
3.5
通讯作者：
Torii, M.
中科院分区：
文献类型：
--
作者：
Oyama, T.;Matsushita, K.;Torii, M.
背景与目的：在牙周炎中，基质金属蛋白酶（MMPs）响应局部释放的炎症细胞因子而上调，导致病理过程。罗红霉素是一种具有广谱抗菌和免疫调节作用的14元环大环内酯类抗生素。最近，我们报道罗红霉素在人牙周韧带（HPDL）细胞培养中抑制肿瘤坏死因子(TNF)- α诱导的血管内皮生长因子的表达。在本研究中，我们检测了罗红霉素对tnf - α诱导的HPDL细胞产生MMP-1的影响。材料和方法：将培养的细胞与1%胎牛血清孵育24 h，然后用10 ng/ml tnf - α、10 μ m罗红霉素和不同浓度的丝裂原活化蛋白激酶抑制剂处理。在不同的时间点收集培养上清和沉积物，用于酶联免疫吸附测定，以及northern和western blot分析。结果：在HPDL细胞培养中，罗红霉素强烈抑制tnf - α诱导的MMP-1 mRNA的表达和产生。罗红霉素对MMP-1基因表达的抑制依赖于从头蛋白合成，并在转录水平上受到调控。罗红霉素显著抑制tnf α诱导的c-Jun n-末端激酶激活（JNP），并轻微抑制细胞外信号调节激酶（ERK） 1/2的激活，但对p38丝裂原激活的蛋白激酶激活没有作用。此外，罗红霉素降低了MMP-1转录的关键因子之一Ets-1的诱导。结论：罗红霉素通过下调ERK1/2和JNK活化以及随后降低Ets-1来抑制tnf - α介导的MMP-1诱导，提示罗红霉素可能在牙周炎和其他涉及MMP-1诱导的慢性炎症疾病中具有治疗作用。
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 mu m 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.