Abstract
Cellular senescence is characterized by a permanent cell-cycle arrest and a pro-inflammatory secretory phenotype, and can be induced by a variety of stimuli, including ionizing radiation, oxidative stress, and inflammation. In endothelial cells, this phenomenon might contribute to vascular disease. Plasma levels of the inflammatory cytokine tumor necrosis factor alpha (TNFα) are increased in age-related and chronic conditions such as atherosclerosis, rheumatoid arthritis, psoriasis, and Crohn’s disease. Although TNFα is a known activator of the central inflammatory mediator NF-κB, and can induce the intracellular generation of reactive oxygen species (ROS), the question whether TNFα can induce senescence has not been answered conclusively. Here, we investigated the effect of prolonged TNFα exposure on the fate of endothelial cells and found that such treatment induced premature senescence. Induction of endothelial senescence was prevented by the anti-oxidant N-acetyl cysteine, as well as by plumericin and PHA-408, inhibitors of the NF-κB pathway. Our results indicated that prolonged TNFα exposure could have detrimental consequences to endothelial cells by causing senescence and, therefore, chronically increased TNFα levels might possibly contribute to the pathology of chronic inflammatory diseases by driving premature endothelial senescence.
Highlights
TNFαis a known activator of NF-κB, and can induce the intracellular generation of ROS31, the question whether prolonged exposure to TNFαcan induce senescence in endothelial cells has not been answered
We addressed this by assessing the proliferative marker Ki-67, the cyclin-dependent kinase inhibitors p16 and p21, as well as components of the aforementioned SASP, namely E-selectin, intracellular adhesion molecule-1 (ICAM-1), plasminogen activator inhibitor-1 (PAI-1), insulin like growth factor binding protein 5 (IGFBP-5) as well as the cytokines IL-6 and IL-8
We studied the effect of two IKK2- targeting inhibitors of NF-κB signaling - the synthetic PHA40833 and the plant-derived plumericin34 - as well as the anti-oxidant N-acetyl cysteine (NAC)[35,36], on the induction of senescence features induced by TNFαin human umbilical vein endothelial cells (HUVECs)
Summary
TNFαis a known activator of NF-κB, and can induce the intracellular generation of ROS31, the question whether prolonged exposure to TNFαcan induce senescence in endothelial cells has not been answered. We investigated whether prolonged stimulation with TNFαmight induce a senescence phenotype in human umbilical vein endothelial cells (HUVECs) in vitro. We addressed this by assessing the proliferative marker Ki-67, the cyclin-dependent kinase inhibitors p16 and p21, as well as components of the aforementioned SASP, namely E-selectin, intracellular adhesion molecule-1 (ICAM-1), plasminogen activator inhibitor-1 (PAI-1), insulin like growth factor binding protein 5 (IGFBP-5) as well as the cytokines IL-6 and IL-8. We studied the effect of two IKK2- targeting inhibitors of NF-κB signaling - the synthetic PHA40833 and the plant-derived plumericin34 - as well as the anti-oxidant N-acetyl cysteine (NAC)[35,36], on the induction of senescence features induced by TNFαin HUVECs
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