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Lipopolysaccharide can trigger a cathepsin B-dependent programmed death response in human endothelial cells
Jie H Li1, Alessio D'Alessio, Jordan S Pober
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520-8089, USA.
The American Journal of Pathology
|August 8, 2009
Summary
Lipopolysaccharide (LPS) triggers programmed cell death in human endothelial cells. This death can be caspase- or cathepsin B-dependent, influenced by various signaling pathways and inhibitors.
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- Lipopolysaccharide (LPS) is a potent immune activator.
- Endothelial cells play critical roles in vascular health and inflammation.
- Understanding LPS-induced cell death mechanisms is crucial for treating inflammatory diseases.
Purpose of the Study:
- To elucidate the molecular mechanisms of lipopolysaccharide (LPS)-induced cell death in human umbilical vein endothelial cells (HUVECs).
- To investigate the roles of caspase-dependent and cathepsin B (Cat B)-dependent pathways in LPS-induced HUVEC death.
- To identify key signaling molecules and pathways involved in LPS-mediated endothelial cell death.
Main Methods:
- Utilized siRNA-mediated knockdown of key proteins like myeloid differentiation factor 88 (MyD88) and Fas-associated death domain protein (FADD).
- Employed proteinase inhibitors and specific pathway inhibitors (e.g., LY294002) to dissect cell death pathways.
- Investigated the effects of protein synthesis inhibition (cycloheximide) and inflammatory cytokines (interferon-gamma) on LPS-induced cell death.
Main Results:
- LPS primarily induces caspase-dependent apoptosis in HUVECs with cycloheximide, dependent on MyD88.
- In FADD-deficient cells, LPS induces a switch to cathepsin B (Cat B)-dependent cell death, independent of MyD88 and Toll-like receptor-associated interferon-inducing factor.
- Phosphatidylinositol 3 kinase (PI3K) inhibition and interferon-gamma modulate LPS-induced cell death pathways, activating both caspase- and Cat B-dependent responses.
Conclusions:
- LPS can activate a Cat B-dependent programmed death response in human endothelial cells.
- This Cat B-dependent death pathway is independent of MyD88 and Toll-like receptor-associated interferon-inducing factor.
- FADD and PI3K signaling pathways play inhibitory roles in the LPS-triggered Cat B death response, while interferon-gamma potentiates it.
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