Proinflammatory cytokine-induced cellular senescence of biliary epithelial cells is mediated via oxidative stress and activation of ATM pathway: A culture study

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-β, IFN-γ and TNF-α) 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.