Lipopolysaccharide can trigger a cathepsin B-dependent programmed death response in human endothelial cells

Alessio D'Alessio, Jh Li, Js Pober

Risultato della ricerca: Contributo in rivistaArticolo in rivista

10 Citazioni (Scopus)

Abstract

In this study, we examined the mechanisms that contribute to lipopolysaccharide (LPS)-induced death responses in cultured human umbilical vein endothelial cells (HUVECs). In the presence of the protein synthesis inhibitor cycloheximide, LPS primarily induces caspase-dependent apoptotic cell death of HUVECs, which is blocked by siRNA-mediated knockdown of myeloid differentiation factor 88 adaptor protein but not of Toll-like receptor-associated interferon-inducing factor. Knockdown of Fas-associated death domain protein (FADD) by either siRNA or overexpression of a truncated version of FADD that lacks the N-terminal death effector domain (FADD(DN)) increases the sensitivity of HUVECs to LPS plus cycloheximide-mediated death. However, based on the use of proteinase inhibitors, cell death changes from being principally caspase-dependent to being principally cathepsin B (Cat B)-dependent. Knockdown of cellular FLICE inhibitory protein potentiates the caspase-dependent pathway but does not activate the Cat B-dependent death response. Knockdown of either myeloid differentiation factor 88 or Toll-like receptor-associated interferon-inducing factor expression does not affect the LPS-triggered Cat B death response in FADD-deficient HUVECs. Finally, in the presence of either the phosphatidylinositol 3 kinase inhibitor LY294002 or the inflammatory cytokine interferon-gamma, LPS activates both caspase- and Cat B-dependent death pathways. We conclude that LPS can activate a Cat-B-dependent programmed death response in human endothelial cells that is independent of both myeloid differentiation factor 88 and Toll-like receptor-associated interferon-inducing factor, is blocked by both FADD and phosphatidylinositol 3 kinase, and is potentiated by interferon-gamma.
Lingua originaleEnglish
pagine (da-a)1124-1135
Numero di pagine12
RivistaTHE AMERICAN JOURNAL OF PATHOLOGY
Volume175
DOI
Stato di pubblicazionePubblicato - 2009

Keywords

  • Apoptosis
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cathepsin B
  • Down-Regulation
  • Endothelial Cells
  • Humans
  • Lipopolysaccharides
  • Phosphatidylinositol 3-Kinases
  • RNA, Small Interfering
  • Umbilical Veins

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