Figure 7. Model of mechanisms involved in TNFα-induced senescence of HUVECs. (A) TNFα activates JAK/STAT and p38 signaling pathways, which mediate increased expression of STAT1/3 phosphorylation. Activation of the JAK pathway leads to persistent phosphorylation of STAT1/3 signaling, which together with ROS, interferon genes, and other SASP components, drives a positive auto-regulatory loop, leading to sustained inflammation and stable senescence. (B) Inhibition of STAT1/3 with the JAK inhibitor AG490 decreased ROS and IL-6 production and decreased expression of interferon response genes. On the other hand, blockade of STAT1/3 expression decreased S phase entry of cells and increased p21 expression, leading to senescence.