Halofuginone induces matrix metalloproteinases in rat hepatic stellate cells via activation of p38 and NFκB
Halofuginone induces matrix metalloproteinases in rat hepatic stellate cells via activation of p38 and NFκB
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DOI：
10.1074/jbc.m600030200
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发表时间：
2006-06-02
影响因子：
4.8
通讯作者：
Schuppan, Detlef
中科院分区：
文献类型：
--
作者：
Popov, Yury;Patsenker, Eleonora;Schuppan, Detlef
据报道，半合成植物生物碱卤常酮 (HAL) 可以预防并部分逆转实验性肝纤维化。然而，人们对它的作用机制知之甚少。因此，我们的目的是确定 HAL 的抗纤维化潜力，并表征肝星状细胞 (HSC) 中涉及的信号转导途径。将结果与逆转硫代乙酰胺诱导的肝纤维化大鼠模型中的体内效果进行比较。体外 HAL 在亚微摩尔浓度下剂量依赖性地抑制 HSC 增殖和迁移。 HAL (200 nM) 将基质金属蛋白酶 (MMP)-3 和 MMP-13 表达上调 10 至 50 倍，导致间质胶原酶活性增加 2 至 3 倍。前胶原 α 1(I) 和 MMP-2 转录水平被抑制 2 至 3 倍，而其他促纤维化 mRNA 的表达不受影响。 HAL 激活 p38 丝裂原激活蛋白激酶 (p38 MAPK) 和核因子 kappa B (NF kappa B) 通路，p38 MAPK 和 NF kappa B 的特异性抑制剂剂量依赖性地抑制 MMP-13 诱导。 HAL 治疗不会影响 HSC 活力，并且观察到的效果在去除后是可逆的。体内 HAL 使肝硬化大鼠的 MMP-3 和 -13 mRNA 表达分别上调 1.5 倍和 2 倍，而金属蛋白酶-1 的组织抑制剂则被抑制 50%。总之，亚微摩尔浓度的 HAL 抑制 HSC 增殖和迁移，并通过激活 p38 MAPK 和 NF kappa B 上调其纤维溶解性 MMP-3 和 -13 的表达。 MMP-3 和 -13 的显着诱导作用使 HAL 成为抗纤维化联合疗法的有前途的药物。
The semisynthetic plant alkaloid halofuginone (HAL) was reported to prevent and partly reverse experimental liver fibrosis. However, its mechanisms of action are poorly understood. We therefore aimed to determine the antifibrotic potential of HAL and to characterize involved signal transduction pathways in hepatic stellate cells (HSCs). Results were compared with its in vivo effects in a rat model of reversal of established liver fibrosis induced by thioacetamide. In vitro HAL inhibited HSC proliferation and migration dose dependently at submicromolar concentrations. HAL ( 200 nM) up-regulated matrix metalloproteinase (MMP)-3 and MMP-13 expression between 10- and 50-fold, resulting in a 2- to 3-fold increase of interstitial collagenase activity. Procollagen alpha 1(I) and MMP-2 transcript levels were suppressed 2- to 3-fold, whereas expression of other profibrogenic mRNAs remained unaffected. p38 mitogen-activated protein kinase ( p38 MAPK) and nuclear factor kappa B (NF kappa B) pathways were activated by HAL, and specific inhibitors of p38 MAPK and NF kappa B dose dependently inhibited MMP-13 induction. Treatment with HAL did not affect HSC viability, and observed effects were reversible after its removal. In vivo HAL up-regulated MMP-3 and -13 mRNA expression 1.5- and 2- fold, respectively, in cirrhotic rats, whereas tissue inhibitor of metalloproteinase-1 was suppressed by 50%. In conclusion, submicromolar concentrations of HAL inhibit HSC proliferation and migration and up-regulate their expression of fibrolytic MMP-3 and -13 via activation of p38 MAPK and NF kappa B. The remarkable induction of MMP-3 and -13 makes HAL a promising agent for antifibrotic combination therapies.