Noda Mami, Kariura Yukihiro, Pannasch Ulrike, Nishikawa Kaori, Wang Liping, Seike Toshihiro, Ifuku Masataka, Kosai Yuki, Wang Bing, Nolte Christiane, Aoki Shunsuke, Kettenmann Helmut, Wada Keiji
Laboratory of Pathophysiology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
J Neurochem. 2007 Apr;101(2):397-410. doi: 10.1111/j.1471-4159.2006.04339.x.
Bradykinin (BK) has been reported to be a mediator of brain damage in acute insults. Receptors for BK have been identified on microglia, the pathologic sensors of the brain. Here, we report that BK attenuated lipopolysaccharide (LPS)-induced release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta from microglial cells, thus acting as an anti-inflammatory mediator in the brain. This effect was mimicked by raising intracellular cAMP or stimulating the prostanoid receptors EP2 and EP4, while it was abolished by a cAMP antagonist, a prostanoid receptor antagonist, or by an inhibitor of the inducible cyclooxygenase (cyclooxygenase-2). BK also enhanced formation of prostaglandin E(2) and expression of microsomal prostaglandin E synthase. Expression of BK receptors and EP2/EP4 receptors were also enhanced. Using physiological techniques, we identified functional BK receptors not only in culture, but also in microglia from acute brain slices. BK reduced LPS-induced neuronal death in neuron-microglia co-cultures. This was probably mediated via microglia as it did not affect TNF-alpha-induced neuronal death in pure neuronal cultures. Our data imply that BK has anti-inflammatory and neuroprotective effects in the central nervous system by modulating microglial function.
据报道，缓激肽（BK）是急性脑损伤中脑损伤的介质。在小胶质细胞（大脑的病理传感器）上已鉴定出BK受体。在此，我们报告BK可减弱脂多糖（LPS）诱导的小胶质细胞释放肿瘤坏死因子-α（TNF-α）和白细胞介素-1β，从而在大脑中作为抗炎介质发挥作用。提高细胞内cAMP或刺激前列腺素受体EP2和EP4可模拟此效应，而cAMP拮抗剂、前列腺素受体拮抗剂或诱导型环氧化酶（环氧化酶-2）抑制剂可消除此效应。BK还增强了前列腺素E2的形成和微粒体前列腺素E合酶的表达。BK受体和EP2/EP4受体的表达也增强。使用生理学技术，我们不仅在培养物中，而且在急性脑片的小胶质细胞中鉴定出功能性BK受体。BK减少了神经元-小胶质细胞共培养物中LPS诱导的神经元死亡。这可能是通过小胶质细胞介导的，因为它不影响纯神经元培养物中TNF-α诱导的神经元死亡。我们的数据表明，BK通过调节小胶质细胞功能在中枢神经系统中具有抗炎和神经保护作用。
