PC-SPES:: A potent inhibitor of nuclear factor-κB rescues mice from lipopolysaccharide-induced septic shock
PC-SPES:: A potent inhibitor of nuclear factor-κB rescues mice from lipopolysaccharide-induced septic shock
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DOI：
10.1124/mol.64.6.1521
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发表时间：
2003-12-01
影响因子：
3.6
通讯作者：
Koeffler, HP
中科院分区：
文献类型：
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作者：
Ikezoe, T;Yang, Y;Koeffler, HP
感染性休克是重症监护病房最常见的死亡原因，目前尚无有效的治疗方法。脂多糖 (LPS) 是革兰氏阴性脓毒症的主要介质，通过诱导巨噬细胞衍生的促炎细胞因子的产生，其中核因子 kappaB (NF-kappaB) 的激活发挥着重要作用。 PC-SPES 是一种八草药混合物，可有效对抗多种恶性肿瘤，包括前列腺癌和白血病。在本研究中，我们证明 PC-SPES 抑制 RAW264.7 巨噬细胞中 LPS 诱导的 NF-kappaB 报告基因活性。电泳迁移率变动分析表明PC-SPES抑制NF-kappaB与特定DNA序列的结合；然而，它不影响抑制性 kappaBalpha 的降解或 NF-kappaB 的核转位。此外，我们还探讨了 PC-SPES 对 LPS 诱导的丝裂原激活蛋白 (MAP) 激酶信号传导的影响； PC-SPES 不影响 LPS 诱导的 MAP 激酶磷酸化，包括 c-Jun NH2 末端激酶、p38 和细胞外信号调节激酶 1/2。此外，在细胞受到 LPS 或 LPS 和干扰素-γ 刺激后，PC-SPES 减少了 C57BL/6 小鼠 RAW264.7 巨噬细胞和腹膜巨噬细胞中促炎细胞因子和诱导酶的产生，例如肿瘤坏死因子 (TNF) α、白细胞介素 (IL)-1β、IL-6、环氧合酶-2 以及诱导型一氧化氮合酶。此外，PC-SPES 使 C57BL/6 小鼠免于因 LPS 诱导的败血性休克以及 TNFα 和 IL-1β 血清水平降低而导致的死亡。总之，PC-SPES 是 NF-kappaB 的有效抑制剂，可能可用于治疗脓毒症和炎症性疾病。
Septic shock is the most common cause of death in intensive care units, and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gram-negative sepsis by inducing the production of macrophage-derived proinflammatory cytokines, in which activation of nuclear factor-kappaB (NF-kappaB) plays an important role. PC-SPES is an eight-herb mixture active against a variety of malignancies, including prostate cancer and leukemia. In this study, we demonstrated that PC-SPES inhibited the LPS-induced NF-kappaB reporter activity in RAW264.7 macrophages. Electrophoretic mobility shift assay showed that PC-SPES inhibited the binding of NF-kappaB to specific DNA sequences; however, it did not affect either degradation of inhibitory kappaBalpha or nuclear translocation of NF-kappaB. Also, we explored the effect of PC-SPES on LPS-induced mitogen-activated protein ( MAP) kinase signaling; PC-SPES did not affect LPS-induced phosphorylation of MAP kinases, including c-Jun NH2-terminal kinase, p38, and extracellular signal-regulated kinase 1/2. Moreover, PC-SPES decreased the production of proinflammatory cytokines and inducible enzymes, such as tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta, IL-6, cyclooxygenase-2, as well as inducible nitric-oxide synthase in RAW264.7 macrophages and peritoneal macrophages from C57BL/6 mice after the cells were stimulated by either LPS or LPS and interferon-gamma. Furthermore, PC-SPES rescued C57BL/6 mice from death caused by LPS-induced septic shock in conjunction with decreased serum levels of TNFalpha and IL-1beta. Together, PC-SPES is a potent inhibitor of NF-kappaB and might be useful for the treatment of sepsis and inflammatory diseases.