Proinflammatory cytokine-induced cellular senescence of biliary epithelial cells is mediated via oxidative stress and activation of ATM pathway: A culture study
Proinflammatory cytokine-induced cellular senescence of biliary epithelial cells is mediated via oxidative stress and activation of ATM pathway: A culture study
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DOI：
10.1080/10715760802244768
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发表时间：
2008-01-01
影响因子：
3.3
通讯作者：
Nakanuma, Yasuni
中科院分区：
文献类型：
--
作者：
Sasaki, Motoko;Ikeda, Hiroko;Nakanuma, Yasuni
据报道，细胞衰老参与原发性胆汁性肝硬化的胆管病变，氧化应激被认为是胆汁上皮细胞（BEC）的致病因素。本研究探讨了促炎细胞因子（IFN-β、IFN-γ和TNF-α）和共济失调毛细血管扩张突变（ATM）/p53/p21（WAF1/Cip1）通路在BEC细胞衰老中的氧化应激作用。H2O2处理（氧化应激）诱导ATM和p53的磷酸化（活化），以及BEC中p21（WAF 1/Cip 1）的表达。用炎性细胞因子处理在培养的BEC中产生活性氧（ROS），随后激活ATM/p53/p21（WAF1/Cip1）通路并诱导细胞衰老。ATM抑制剂（2-氨基嘌呤）和抗氧化剂（N-乙酰半胱氨酸）预处理可显著阻断氧化应激或炎性细胞因子诱导的BEC细胞衰老。总之，促炎性细胞因子诱导ROS产生并激活ATM/p53/p21（WAF 1/Cip 1）通路，随后是胆管上皮衰老。这种衰老过程可能与人类破坏性胆管病的发展有关。
Cellular senescence is reportedly involved in cholangiopathy in primary biliary cirrhosis and oxidative stress is proposed as a pathogenetic factor in biliary epithelial cells (BECs). This study investigated the involvement of proinflammatory cytokines (IFN-beta, IFN-gamma and TNF-alpha) and ataxia telangiectasia-mutated (ATM)/p53/p21(WAF1/Cip1) pathway with respect to oxidative stress in cellular senescence of BECs. H2O2 treatment (oxidative stress) induced phosphorylation (activation) of ATM and p53 and also p21(WAF1/Cip1) expression in BECs. Treatment with inflammatory cytokines generated reactive oxygen species (ROS) in cultured BECs followed by activation of the ATM/p53/p21(WAF1/Cip1) pathway and the induction of cellular senescence. Pre-treatment with ATM inhibitor (2-aminopurine) and antioxidant (N-acetylcysteine) significantly blocked the cellular senescence of BECs induced by oxidative stress or inflammatory cytokines. In conclusion, proinflamamtory cytokines induce ROS generation and activate the ATM/p53/p21(WAF1/Cip1) pathway, followed by biliary epithelial senescence. This senescent process may be involved in the development of destructive cholangiopathy in humans.