Interferon-γ induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells

Dec 17, 2008Mechanisms of ageing and development

Interferon-gamma may cause human blood vessel cells to age by triggering DNA damage through p53

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Abstract

Prolonged treatment with IFN-gamma induced cellular senescence in human umbilical vascular endothelial cells (HUVECs).

Cellular senescence is characterized by loss of proliferation, G0/G1 cell cycle arrest, and increased levels of specific proteins.
Alterations in interferons (IFNs) and IFN-inducible genes were noted during replicative senescence in HUVECs.
IFN-gamma-induced senescence was confirmed by increased SA-beta-gal staining and accumulation of DNA damage markers.
This effect was observed in cells lacking p16 but not in those lacking p53, suggesting a specific dependency.
Increased production of reactive oxygen species (ROS) was associated with IFN-gamma treatment, which could be mitigated by antioxidants.
Knockdown of ATM kinase or IFI16 was found to rescue the senescence induced by IFN-gamma.

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Cellular senescence is a stress-response phenomenon in which cells lose the ability to proliferate; it is induced by telomere shortening, activation of oncogenes or tumor suppressor genes, or exposure to a sub-lethal dose of DNA damaging agents or oxidative stresses. cDNA microarray analysis reveals that the levels of interferons (IFNs) and IFN-inducible genes were altered during replicative senescence in human umbilical vascular endothelial cells (HUVECs). However, the role of IFNs in cellular senescence of HUVECs remains unidentified. This study demonstrated that prolonged treatment with IFN-gamma induced cellular senescence in HUVECs, as confirmed by G0/G1 cell cycle arrest, up-regulation of p53 and p21 protein levels, increased SA-beta-gal staining, and the accumulation of phospho-H(2)AX foci. IFN-gamma-induced cellular senescence was observed only in p16-knockdown cells or p16-null mouse embryonic fibroblasts (MEFs), but not in p53-knockdown cells or p53-null MEFs. IFN-gamma treatment increased ROS production, and an antioxidant, N-acetylcysteine, inhibited IFN-gamma-induced cellular senescence. Knockdown of ATM kinase or IFI16 rescued IFN-gamma-induced cellular senescence. Therefore, these results suggest that IFN-gamma might play an important role in cellular senescence through a p53-dependent DNA damage pathway and contribute to the pathogenesis of atherosclerosis via its pro-senescent activity.

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Interferon-γ induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells

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