The Fas-FasL death receptor and Pl3K pathways independently regulate monocyte homeostasis

Harris Perlman, Lisa J. Pagliari, Nadine Nguyen, Kathleen Bradley, Hongtao Liu, Richard M. Pope*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Peripheral blood-derived monocytes spontaneously undergo apoptosis mediated by Fas-Fas ligand (FasL) interactions. Activation of monocytes by LPS or TNF-α prevents spontaneous monocyte apoptosis through an unknown mechanism. Here, we demonstrate that LPS and TNF-α up-regulate Flip and suppress spontaneous Fas-FasL mediated monocyte apoptosis and caspase 8 and 3 activation. Flip was responsible for this protection, since inhibition of Flip by antisense oligonucleotides in the presence of LPS or TNF-α restored monocyte sensitivity to spontaneous apoptosis. We also investigated whether the PI3K pathway contributes to the suppression of spontaneous monocyte apoptosis mediated by LPS and TNF-α. Monocytes treated with a reversible PI3K inhibitor (LY294002) displayed enhanced apoptosis, while LPS and TNF-α partially protected against apoptosis mediated by LY294002. However, direct suppression of Fas-FasL interactions by addition of neutralizing anti-FasL antibody did not further suppress LY294002-induced apoptosis in the presence of LPS or TNF-α. Collectively, these data demonstrate that LPS or TNF-α protect monocytes from death receptor-mediated apoptosis through the up-regulation of Flip, but not apoptosis initiated by inhibition of the PI3K pathway.

Original languageEnglish (US)
Pages (from-to)2421-2430
Number of pages10
JournalEuropean Journal of Immunology
Volume31
Issue number8
DOIs
StatePublished - 2001

Keywords

  • Apoptosis
  • CD95 (APO-1/Fas)
  • Flip
  • Monocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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