Department of Pharmacology, Brain Science and Engineering Institute, CMRI, Kyungpook National University School of Medicine, Daegu, Korea.
J Neurosci Res. 2010 Aug 1;88(10):2188-96. doi: 10.1002/jnr.22378.
Glucocorticoid-induced tumor necrosis factor receptor family-related protein ligand (GITRL) is a member of the tumor necrosis factor superfamily (TNFSF) and is known to act as a costimulator in the immune system by binding to GITR. GITRL is expressed in endothelial cells, dendritic cells, macrophages, and B cells, but it is not known whether GITRL is expressed in brain microglia cells. Here, we investigated the expression of GITR and GITRL and their potential role in microglia cells. Using BV-2 mouse microglia cells and mouse primary microglia cultures, we have demonstrated that 1) both GITR and GITRL are expressed in microglia cells; 2) stimulation of GITRL induces inflammatory activation of microglia on the basis of production of nitric oxide (NO) and expression of inducible nitric oxide synthase, cyclooxygenase-2, CD40, and matrix metalloproteinase-9; 3) GITRL-mediated microglial NO production partially depends on p38 MAPK, JNK, and nuclear factor-kappaB pathways; and 4) GITRL stimulation also induces microglia cell death. These results indicate that GITR and GITRL are functionally expressed on brain microglia and that the stimulation of GITRL can induce inflammatory activation of microglia. The GITR/GITRL system may play an important role in neuroinflammation.
糖皮质激素诱导的肿瘤坏死因子受体家族相关蛋白配体（GITRL）是肿瘤坏死因子超家族（TNFSF）的一员，已知通过与 GITR 结合在免疫系统中充当共刺激物。GITRL 在血管内皮细胞、树突状细胞、巨噬细胞和 B 细胞中表达，但尚不清楚 GITRL 是否在脑小胶质细胞中表达。在这里，我们研究了 GITR 和 GITRL 的表达及其在小胶质细胞中的潜在作用。使用 BV-2 小鼠小胶质细胞和小鼠原代小胶质细胞培养物，我们已经证明：1）GITR 和 GITRL 均在小胶质细胞中表达；2）GITRL 的刺激会基于一氧化氮（NO）的产生和诱导型一氧化氮合酶、环加氧酶-2、CD40 和基质金属蛋白酶-9 的表达，诱导小胶质细胞的炎症激活；3）GITRL 介导的小胶质细胞 NO 产生部分依赖于 p38 MAPK、JNK 和核因子-kappaB 途径；4）GITRL 刺激也会诱导小胶质细胞死亡。这些结果表明，GITR 和 GITRL 在脑小胶质细胞上功能性表达，并且 GITRL 的刺激可以诱导小胶质细胞的炎症激活。GITR/GITRL 系统可能在神经炎症中发挥重要作用。
