, Volume 19, Issue 3–4, pp 237–249 | Cite as

Long-term exposure to TNF-α leads human skin fibroblasts to a p38 MAPK- and ROS-mediated premature senescence

  • Eleni Mavrogonatou
  • Angeliki Konstantinou
  • Dimitris Kletsas
Research Article


Tumor necrosis factor α (TNF-α) is an inflammatory mediator overexpressed in the skin as a response to ultraviolet radiation, as well as in chronic non-healing wounds. On the other hand, senescent fibroblasts have been shown to accumulate in the skin under these stressful conditions. Accordingly, here we assessed the putative implication of TNF-α in the induction of premature senescence of human adult dermal fibroblasts. We showed that TNF-α led to a rapid transient p38 MAPK activation, while elevation of reactive oxygen species (ROS) only occurred after a chronic exposure to TNF-α. Furthermore, in contrast to the majority of previous reports using various cell models and experimental settings, it was a long-term treatment with TNF-α that resulted in the premature senescence of human dermal fibroblasts, as shown by the reduced proliferative potential and the increased senescence associated β-galactosidase staining of the cells. TNF-α-senescent cells displayed a permanent phosphorylation of p38 MAPK and an inflammatory and catabolic phenotype. Increased ROS levels were also observed, possibly attributed to the weakened anti-oxidative response evidenced by the underexpression of the Nrf2-regulated genes encoding HO-1 and NQO1. These traits and the overall senescent phenotype were significantly reversed using the known anti-oxidant N-acetyl-l-cysteine or a specific p38 MAPK inhibitor, suggesting the participation of oxidative stress and of the p38 MAPK pathway in TNF-α-triggered premature senescence. Even more, the observed blockade of ROS accumulation in senescent skin fibroblasts by p38 MAPK inhibition indicates a possible link between these two separate events during the manifestation of TNF-α-induced senescence.


Dermal fibroblasts Inflammation Wound SA-β Gal p16INK4a Proliferation Nrf2 MMPs HO-1 NQO1 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Eleni Mavrogonatou
    • 1
  • Angeliki Konstantinou
    • 1
  • Dimitris Kletsas
    • 1
  1. 1.Laboratory of Cell Proliferation and Ageing, Institute of Biosciences and ApplicationsNational Centre for Scientific Research “Demokritos”AthensGreece

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