Sphingosine kinase 1 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta1.
Sphingosine kinase 1 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta1.
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发表时间：
2007
影响因子：
6.4
通讯作者：
Y. Kono;T. Nishiuma;Y. Nishimura;Y. Kotani;T. Okada;Shun-ichi Nakamura;M. Yokoyama
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文献类型：
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作者：
Y. Kono;T. Nishiuma;Y. Nishimura;Y. Kotani;T. Okada;Shun-ichi Nakamura;M. Yokoyama
转化生长因子-β(TGF-β)通过上调α-平滑肌肌动蛋白(α-SMA)作为肺成纤维细胞分化而参与肺纤维化的进展。生物活性的1-磷酸鞘氨醇(S1P)可以模拟转化生长因子-β信号，然而，S1P在肺纤维化过程中的作用还没有很好的文献报道。我们发现，在博莱霉素肺纤维化的小鼠模型中，SPHK1和α-SMA共存于肺纤维化灶中，并且这些表达在原代培养的成纤维细胞中显著增加。利用人肺成纤维细胞WI-38，我们探讨了转化生长因子-β1刺激的鞘氨醇激酶(SPHK)的作用机制。SPHK抑制剂和针对SPHK1的小干扰RNA(SiRNA)可降低由转化生长因子-β1上调的α-SMA和纤维连接蛋白的表达。同时，抑制SPHK1并不影响Smad2对转化生长因子-β1的磷酸化反应。然后我们研究了S1P受体反式激活是否会影响转化生长因子-β信号。针对S1P(2)和S1P(3)的siRNA，而不是S1P(1)，可降低α-SMA的表达，并减少Rho激酶抑制剂Y-27632的表达。在S1P(2)或S1P(3)高表达的细胞膜上，我们还检测到在转化生长因子-β1刺激下Rho GTP酶的激活。这些结果提示，在肺纤维化过程中，转化生长因子-β1激活SPHK1可通过反式激活的S1P受体介导Rho相关的肌成纤维细胞分化。
Transforming growth factor beta (TGF-beta) contributes to the progression of pulmonary fibrosis through up-regulation of alpha-smooth muscle actin (alpha-SMA) as lung myofibroblast differentiation. Bioactive sphingosine 1-phosphate (S1P) has been shown to mimic TGF-beta signals; however, the function of S1P in lung fibrotic process has not been well documented. We found, in a mouse model of bleomycin lung fibrosis, that SPHK1 and alpha-SMA were colocalized within lung fibrotic foci and that these expressions were significantly increased in primary cultured fibroblasts. Using human lung fibroblasts WI-38, we explored the rationale of sphingosine kinase (SPHK) with TGF-beta1 stimulation. SPHK inhibitors and small interference RNA (siRNA) targeted SPHK1 decreased alpha-SMA and fibronectin expression up-regulated by TGF-beta1. In the meantime, SPHK1 inhibition did not affect smad2 phosphorylation in response to TGF-beta1. Then we examined whether S1P receptors transactivation may affect TGF-beta signals. siRNA against S1P(2) and S1P(3), but not S1P(1), reduced alpha-SMA expression as well as Y-27632, Rho kinase inhibitor. We also detected activation of Rho GTPase upon stimulation of TGF-beta1 on the cell membrane where S1P(2) or S1P(3) was overexpressed. These data suggested that SPHK1 activation by TGF-beta1 leads to Rho-associated myofibroblasts differentiation mediated by transactivated S1P receptors in the lung fibrogenic process.