Cryptotanshinone inhibits chemotactic migration in macrophages through negative regulation of the PI3K signaling pathway
Cryptotanshinone inhibits chemotactic migration in macrophages through negative regulation of the PI3K signaling pathway
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DOI：
10.1038/sj.bjp.0707271
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发表时间：
2007-07-01
影响因子：
7.3
通讯作者：
Chiou, W-F
中科院分区：
文献类型：
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作者：
Don, M-J;Liao, J-F;Chiou, W-F
背景与目的：隐丹参酮是从丹参中分离得到的主要丹参酮，具有抗肿瘤活性。然而，没有关于隐丹参酮对白细胞向炎症部位募集的作用的报道。因此，我们评估了隐丹参酮对巨噬细胞趋化性的影响。实验方法：在体外测量由补体5a（C5 a）或巨噬细胞炎性蛋白-1 α（MIP-1 α）诱导的巨噬细胞迁移。关键结果：隐丹参酮（1、3、10和30 μ M）以浓度依赖性方式显著抑制RAW264.7细胞向C5 a（1 μ g/ml-1 α）的迁移。由C5 a刺激的原代人巨噬细胞被类似地抑制。Wortmannin可显著抑制C5 a诱导的RAW264.7细胞迁移（磷脂酰肌醇3-激酶（PI 3 K）抑制剂），PD 98059（MEK 1/2抑制剂）和SB 203580（p38丝裂原活化蛋白激酶（MAPK）抑制剂），但不是由SP 600125（c-Jun N-末端激酶（JNK）抑制剂），表明PI 3 K、ERK 1/2和p38 MAPK信号通路的激活参与了对C5 a的应答。Western blotting结果显示隐丹参酮显著抑制C5 a诱导的PI 3 K-p110 γ膜转位及Akt和ERK 1/2的磷酸化。隐丹参酮对p38 MAPK和JNK磷酸化均无影响。Wortmannin显著减弱C5 a诱导的PI 3 K-p110 γ易位、Akt和ERK 1/2磷酸化。PD 98059抑制ERK 1/2磷酸化，但不能通过C5 a刺激改变PI 3 K-p110 γ易位。此外，MIP-1 α诱导的细胞迁移和PI 3 K-p110 γ易位也被抑制隐丹参酮在一个浓度依赖性mathematic.Conclusions和影响：隐丹参酮参与抑制巨噬细胞迁移的PI 3 K活化，从而减少Akt和ERK 1/2的磷酸化。
Background and purpose: Cryptotanshinone, the major tanshinone isolated from Salvia miltiorrhiza Bunge, exhibits antiinflammatory activity. However, there is no report on the effect of cryptotanshinone on recruitment of leukocytes to inflammatory sites. We therefore assessed the effects of cryptotanshinone on macrophage chemotaxis.Experimental approach: Macrophage migration induced by complement 5a (C5a) or macrophage inflammatory protein-1 alpha (MIP-1 alpha) was measured in vitro. Intracellular kinase translocation and phosphorylation was assessed by Western blotting.Key results: RAW264.7 cell migration towards C5a (1 mu gml-1 alpha) was significantly inhibited by cryptotanshinone (1, 3, 10 and 30 mu M) in a concentration- dependent manner. Primary human macrophages stimulated by C5a were similarly inhibited. C5a-evoked migration in RAW264.7 cells was significantly suppressed by wortmannin (phosphatidylinositol 3-kinase (PI3K) inhibitor), PD98059 (MEK1/2 inhibitor) and SB203580 (p38 mitogen- activated protein kinase (MAPK) inhibitor), but not by SP600125 (c-Jun N-terminal kinase (JNK) inhibitor), suggesting that activation of PI3K, ERK1/2 and p38 MAPK signal pathways was involved in responses to C5a. Western blotting revealed that cryptotanshinone significantly inhibited PI3K-p110 gamma membrane translocation and phosphorylation of Akt (PI3K downstream effector protein) and ERK1/2 induced by C5a. However, neither p38 MAPK nor JNK phosphorylation was affected by cryptotanshinone. Wortmannin significantly attenuated C5a-induced PI3K-p110 gamma translocation, Akt and ERK1/2 phosphorylation. PD98059 suppressed ERK1/2 phosphorylation but failed to modify PI3K-p110 gamma translocation by C5a stimulation. Furthermore, MIP-1 alpha-induced cell migration and PI3K-p110 gamma translocation were also inhibited by cryptotanshinone in a concentration-dependent manner.Conclusions and implications: Inhibition of macrophage migration by cryptotanshinone involved inhibition of PI3K activation with consequent reduction of phosphorylation of Akt and ERK1/2.