The Fas/FasL apoptotic pathway is involved in kappa-opioid-induced apoptosis of human endometrial stromal cells

Mol Hum Reprod. 2001 Sep;7(9):867-74. doi: 10.1093/molehr/7.9.867.

Abstract

Human endometrium expresses specific kappa-opioid binding sites and their endogenous ligands, the dynorphins. In neural crest-derived tissues, kappa-opioids affect apoptosis, a phenomenon of major significance in endometrial stroma physiology. Our hypothesis was that endometrial kappa-opioids may play a role in endometrial stromal cell apoptosis. Thus, we examined the effect of the synthetic kappa-opioid agonist, U69593, on the apoptotic rate of human endometrial stromal cells in primary culture. Apoptosis of endometrial stromal cells was elevated after 3 h exposure to 100 nmol/l U69593, and remained elevated for up to 3 days. This effect was dose-dependent and was reversed by the general opioid antagonist, naloxone, suggesting that it is mediated via opioid receptors. In parallel, semi-quantitative Western blot and flow cytometry analysis showed that U69593 caused a rapid but transient up-regulation of Fas protein, suggesting that its effect on apoptosis is mediated by activation of the Fas/FasL apoptotic pathway. Additionally, U69593 increased the content of the anti-apoptotic members of the Bcl-2 family of proteins, the Bcl-2 and Bcl-x(L), whereas it had no significant effect on the apoptosis-promoting homologues Bax, Bcl-x(S) and Bak. This implies that a transient survival mechanism is activated in stromal cells as a parallel rescue response to the apoptosis-inducing factor. In conclusion, our data suggest that endometrial opioid dynorphins may participate in the apoptotic processes related to endometrial tissue remodelling during early pregnancy or menstruation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / drug effects
  • Benzeneacetamides*
  • Cells, Cultured
  • Endometrium / cytology*
  • Endometrium / drug effects
  • Fas Ligand Protein
  • Female
  • Humans
  • Ligands
  • Membrane Glycoproteins / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrrolidines / pharmacology
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / physiology*
  • Signal Transduction* / drug effects
  • Stromal Cells / cytology
  • Stromal Cells / drug effects
  • fas Receptor / metabolism*

Substances

  • Benzeneacetamides
  • FASLG protein, human
  • Fas Ligand Protein
  • Ligands
  • Membrane Glycoproteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • fas Receptor
  • U 69593