Search

Secretory phospholipase A2 (sPLA2) is involved in various cellular physiological and pathological responses, especially in inflammatory responses. Accumulating evidence suggests that inflammation is an underlying basis for the molecular alterations that link aging and age-related pathological processes. However, the involvement of sPLA2 in cellular senescence is not clear. In this study, we found that sPLA2 treatment induces cellular senescence in human dermal fibroblasts (HDFs), as confirmed by increases in senescence-associated β-galactosiclase activity, changes in cell morphology, and upregulation of p53/p21 protein levels. sPLA2-induced senescence was observed in p16-knockdown HDFs and p16-null mouse fibroblasts, but not in p53-knockdown HDFs and p53-null mouse fibroblasts. Treatment with sPLA2 increases reactive oxygen species (ROS) production, and an antioxidant, N-acetylcysteine inhibits sPLA2-induced cellular senescence. These results suggest that sPLA2 has a role in cellular senescence in HDFs during inflammatory response by promoting ROS-dependent p53 activation and might therefore contribute to inflammatory disorders associated with aging. [ABSTRACT FROM AUTHOR]

The signaling pathway of insulin/insulin-like growth factor/phosphatidylinositol-3 kinase/Akt/forkhead transcription factors is known to control life span and senescence in organisms ranging from yeast to mice. The FOXO family of forkhead transcription factors, FOXO1, FOXO3a, and FOXO4, play a critical role in this signal transduction pathway. However, the impact of FOXO3a activation on life span of primary cultured human dermal fibroblasts (HDFs) is unknown. To investigate the role of FOXO3a in the regulation of cellular senescence, we prepared FOXO3a-siRNA stable HDFs. We found that the down-regulation of FOXO3a RNA and protein in HDFs induced many senescent phenotypes, including changes in cell morphology, increases in population doubling times, senescence-associated β-galactosidase staining and the cellular reactive oxygen species, and up-regulation of p53/p21 protein expression. Our data provide evidence of the key role of FOXO3a transcription factor as a mediator of cellular senescence in HDFs, and suggest that the mechanism of senescence is conserved in HDFs. [ABSTRACT FROM AUTHOR]