Giuliani Fabrizio, Hader Walter, Yong V Wee
Department of Clinical Neurosciences, University of Calgary, Alberta, Canada.
J Leukoc Biol. 2005 Jul;78(1):135-43. doi: 10.1189/jlb.0804477. Epub 2005 Apr 7.
Minocycline, a tetracycline with anti-inflammatory properties, has been reported to down-regulate the activity of microglia, whose activation occurs in inflammatory and degenerative diseases of the central nervous system, such as multiple sclerosis and Alzheimer's disease. In these disorders, a T cell component is also evident, and we have demonstrated previously that the interaction of activated T cells with microglia led to the substantial increase in tumor necrosis factor alpha (TNF-alpha) levels. Here, we report that minocycline decreases TNF-alpha levels produced in human T cell-microglia interaction. This effect is mediated by a direct action of minocycline on the activated T cells and on microglia, which resulted in the decreased ability of T cells to contact microglia. In correspondence, minocycline decreased the expression on T cells of the CD40 ligand (CD40L), a key molecule regulating the contact-mediated interaction of T cells with microglia. These results demonstrate that the mechanism of action of minocycline involves not only microglia but also T cells and their subsequent activation of microglia. The capacity of minocycline to down-regulate CD40L on T cells may provide a new means to target the CD40-CD40L pathway, which regulates several inflammatory processes.
米诺环素是一种具有抗炎特性的四环素类药物，据报道它能下调小胶质细胞的活性，小胶质细胞的激活发生在中枢神经系统的炎症和退行性疾病中，如多发性硬化症和阿尔茨海默病。在这些疾病中，T细胞成分也很明显，并且我们之前已经证明活化的T细胞与小胶质细胞的相互作用会导致肿瘤坏死因子α（TNF-α）水平大幅升高。在此，我们报告米诺环素可降低人T细胞与小胶质细胞相互作用产生的TNF-α水平。这种作用是由米诺环素对活化的T细胞和小胶质细胞的直接作用介导的，这导致T细胞与小胶质细胞接触的能力下降。相应地，米诺环素降低了T细胞上CD40配体（CD40L）的表达，CD40L是调节T细胞与小胶质细胞接触介导相互作用的关键分子。这些结果表明米诺环素的作用机制不仅涉及小胶质细胞，还涉及T细胞及其随后对小胶质细胞的激活。米诺环素下调T细胞上CD40L的能力可能为靶向调节多种炎症过程的CD40 - CD40L途径提供一种新方法。
