TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion

Renuka Kandhaya-Pillai, Francesc Miro-Mur, Jaume Alijotas-Reig, Tamara Tchkonia, James L. Kirkland, Simo Schwartz

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Cellular senescence is a cell fate program that entails essentially irreversible proliferative arrest in response to damage signals. Tumor necrosis factor-alpha (TNFα), an important pro-inflammatory cytokine secreted by some types of senescent cells, can induce senescence in mouse and human cells. However, downstream signaling pathways linking TNFα-related inflammation to senescence are not fully characterized. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that TNFα induces permanent growth arrest and increases p21CIP1, p16INK4A, and SA-β-gal, accompanied by persistent DNA damage and ROS production. By gene expression profiling, we identified the crucial involvement of inflammatory and JAK/STAT pathways in TNFα-mediated senescence. We found that TNFα activates a STAT-dependent autocrine loop that sustains cytokine secretion and an interferon signature to lock cells into senescence. Furthermore, we show STAT1/3 activation is necessary for cytokine and ROS production during TNFα-induced senescence. However, inhibition of STAT1/3 did not rescue cells from proliferative arrest, but rather suppressed cell cycle regulatory genes and altered TNFα-induced senescence. Our findings suggest a positive feedback mechanism via the STAT pathway that sustains cytokine production and reveal a reciprocal regulatory role of JAK/STAT in TNFα-mediated senescence.

Original languageEnglish (US)
Pages (from-to)2411-2435
Number of pages25
JournalAging
Volume9
Issue number11
DOIs
StatePublished - 2017

Keywords

  • DNA-damage
  • Inflammation
  • Interferon response genes
  • JAK/STAT pathway
  • Senescence

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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