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. (Am J Pathol 2009, 175:1124-1135; DOI. 10.2353/ajpath.2009.090113)

Lipopolysaccharide Can Trigger a Cathepsin B-Dependent Programmed Death Response in Human Endothelial Cells / J. I. E. H., Li; D'Alessio, Alessio; S., Pober Jordan. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - 175:3(2009), pp. 1124-1135. [10.2353/ajpath.2009.090113]

Lipopolysaccharide Can Trigger a Cathepsin B-Dependent Programmed Death Response in Human Endothelial Cells

D'ALESSIO, ALESSIO;
2009

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. (Am J Pathol 2009, 175:1124-1135; DOI. 10.2353/ajpath.2009.090113)
2009
01 Pubblicazione su rivista::01a Articolo in rivista
Lipopolysaccharide Can Trigger a Cathepsin B-Dependent Programmed Death Response in Human Endothelial Cells / J. I. E. H., Li; D'Alessio, Alessio; S., Pober Jordan. - In: THE AMERICAN JOURNAL OF PATHOLOGY. - ISSN 0002-9440. - 175:3(2009), pp. 1124-1135. [10.2353/ajpath.2009.090113]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/349256
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