N-acetylcysteine induces cell cycle arrest in hepatic stellate cells through its reducing activity
N-acetylcysteine induces cell cycle arrest in hepatic stellate cells through its reducing activity
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DOI：
10.1074/jbc.m100975200
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发表时间：
2001-11-02
影响因子：
4.8
通讯作者：
Kim, SS
中科院分区：
文献类型：
--
作者：
Kim, KY;Rhim, T;Kim, SS
肝星状细胞（hepatic stellate cell，HSC）的活化是肝纤维化发生的关键步骤，受细胞因子和氧化应激等多种因素的调控。然而，HSC失活的分子机制还不清楚。我们研究了参与HSC失活的N-乙酰基-L-半胱氨酸（NAC）介导的信号通路。NAC通过其还原活性起作用，以Ras非依赖性方式经由丝裂原活化蛋白激酶（MAPK）激酶（MEK）/ MAPK途径诱导细胞在G1期停滞。这种细胞外信号调节激酶的持续激活诱导细胞周期依赖性激酶抑制剂p21（Cip/WAF 1）的表达，并通过Spl转录激活因子依赖性机制介导细胞生长停滞。NAC的这些作用都被逆转治疗的HSC与MEK抑制剂PD 98059，然后培养HSC的I型胶原包被的烧瓶。胶原介导的NAC诱导的细胞周期停滞的抑制可能是由于通过加速整合素诱导的细胞生长而导致的细胞周期停滞。NAC的作用实际上依赖于调节靶蛋白如Raf-1、MEK和ERK的半胱氨酸残基的氧化还原状态。总之，对HSC中NAC信号通路的理解应该为临床上使用抗氧化剂治疗肝纤维化提供理论基础。
Activation of hepatic stellate cells (HSC) has been identified as a critical step in hepatic fibrogenesis and is regulated by several factors including cytokines and oxidative stress. However, the molecular mechanism for HSC inactivation is not well understood. We investigated an N-acetyl-L-cysteine (NAC)-mediated signaling pathway involved in HSC inactivation. NAC, which acting through its reducing activity, induced cell arrest at Gl via the mitogen-activated protein kinase (MAPK) kinase (MEK)/ MAPK pathway in a Ras-independent manner. The sustained activation of this extracellular signal-regulated kinase induced the expression of p21(Cip/WAF1), a cell cycle-dependent kinase inhibitor, and mediated cell growth arrest through the Spl transcription activator-dependent mechanism. These effects of NAC were all reversed by treatment of HSC with MEK inhibitor PD98059 followed by culturing HSC on type I collagen-coated flasks. The collagen-mediated suppression of NAC-induced arrest may be due to an overriding of the cell cycle arrest through an acceleration of integrin-induced cell growth. NAC action is actually dependent on modulating the redox states of cysteine residues of target proteins such as Raf-1, MEK, and ERK. In conclusion, an understanding of the NAC signaling pathway in HSC should provide the theoretical basis for clinical approaches using antioxidant therapies in liver fibrosis.