FLICE-inhibitory protein expression during macrophage differentiation confers resistance to Fas-mediated apoptosis

Harris Perlman, Lisa J. Pagliari, Constantinos Georganas, Toshiaki Mano, Kenneth Walsh, Richard M. Pope*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

213 Scopus citations

Abstract

Macrophages differentiated from circulating peripheral blood monocytes are essential for host immune responses and have been implicated in the pathogenesis of rheumatoid arthritis and atherosclerosis. In contrast to monocytes, macrophages are resistant to Fas-induced celt death by an unknown mechanism. FLICE (Fas-associated death domain-like interleukin 1β-converting enzyme)-inhibitory protein (Flip), a naturally occurring caspase-inhibitory protein that lacks the critical cysteine domain necessary for catalytic activity, is a negative regulator of Fas-induced apoptosis. Here, we show that monocyte differentiation into macrophages was associated with upregulation of Flip and a decrease in Fas-mediated apoptosis. Overexpression of Flip protected monocytes from Fas-mediated apoptosis, whereas acute Flip inhibition in macrophages induced apoptosis. Addition of an antagonistic Fas ligand antibody to Flip antisense-treated macrophages rescued cultures from apoptosis, demonstrating that endogenous Flip blocked Fas-induced cell death. Thus, the expression of Flip in macrophages conferred resistance to Fas- mediated apoptosis, which may contribute to the development of inflammatory disease.

Original languageEnglish (US)
Pages (from-to)1679-1688
Number of pages10
JournalJournal of Experimental Medicine
Volume190
Issue number11
DOIs
StatePublished - Dec 6 1999

Keywords

  • Apoptosis
  • Fas
  • Flip
  • Macrophages
  • Monocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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