DOXYCYCLINE AND MINOCYCLINE INHIBIT INFLAMMATORY RESPOSES TO B BURGDORFERI

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 四环素类药物可缓解各种病因引起的炎症反应。我们假设四环素类药物除了抗菌功能外，还能控制伯氏疏螺旋体引起的炎症。为了模拟全身效应，我们使用人单核细胞系THP-1，并且对于中枢神经系统中的效应，我们使用恒河猴脑星形胶质细胞和小胶质细胞。用活的或超声处理的B刺激细胞。在递增浓度的多西环素或米诺环素存在的情况下，在所有细胞类型中，两种抗生素均以剂量依赖性方式显著降低TNF-α、IL-6和IL-8的产生。在螺旋体刺激的单核细胞中，多西环素对基因转录影响的微阵列分析显示NF B和IKK-α基因下调。在功能上，在这些细胞中，I <$B-α的磷酸化和NF <$B与靶DNA的结合都减少了。我们的结果证明了四环素类药物对莱姆病可能具有双重治疗作用的原则。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tetracyclines moderate inflammatory responses of various etiologies. We hypothesized that tetracyclines exerted, in addition to antimicrobial function, control over inflammation elicited by Borrelia burgdorferi. To model systemic effects we used the human monocytic cell line THP-1, and for effects in the central nervous system we employed rhesus monkey brain astrocytes and microglia. Cells were stimulated with live or sonicated B. burgdorferi, or the OspA lipoprotein, in the presence of increasing concentrations of doxycycline or minocycline. Both antibiotics significantly reduced the production of TNF-alpha, IL-6, and IL-8 in a dose-dependent manner in all cell types. Microarray analyses of the effect of doxycycline on gene transcription in spirochete-stimulated monocytes revealed that the NF¿B and IKK-alpha genes were down-regulated. Functionally, phosphorylation of I¿B-alpha and binding of NF¿B to target DNA were both reduced in these cells. Our results prove the principle that tetracyclines may have a dual therapeutic effect in Lyme disease.