DOXYCYCLINE AND MINOCYCLINE INHIBIT INFLAMMATORY RESPOSES TO B BURGDORFERI

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 四环素类药物可缓解各种原因的炎症反应。我们推测，除了抗菌功能外，四环素还可以控制伯氏疏螺旋体引起的炎症。为了模拟全身性效应，我们使用了人类单核细胞系THP-1，而对于中枢神经系统的效应，我们使用了恒河猴脑星形胶质细胞和小胶质细胞。在浓度增加的多西环素或米诺环素存在的情况下，用活的或超声处理的伯氏杆菌或OspA脂蛋白刺激细胞。两种抗生素均以剂量依赖的方式显著减少所有细胞类型的肿瘤坏死因子-α、白介素6和白介素8的产生。基因芯片分析了多西环素对螺旋体刺激的单核细胞基因转录的影响，结果显示，核因子B和IKK-α基因表达下调。在功能上，这些细胞中I？B-α的磷酸化和核因子B与靶DNA的结合均减少。我们的结果证明了四环素可能对莱姆病具有双重治疗作用的原理。

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.