A Constitutive Cytoprotective Pathway Protects Endothelial Cells from Lipopolysaccharide-induced Apoptosis
| Autor: | Robert K. Winn, William Ricketts, C. Frank Bennett, Joan C. Tupper, John M. Harlan, Douglas D. Bannerman |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Lipopolysaccharides
Proteasome Endopeptidase Complex Endothelium Cell Survival Lactacystin CASP8 and FADD-Like Apoptosis Regulating Protein Apoptosis Cycloheximide Biology Biochemistry chemistry.chemical_compound Multienzyme Complexes medicine Humans Molecular Biology Cells Cultured DNA Primers Inhibitor of apoptosis domain Base Sequence Tumor Necrosis Factor-alpha Hydrolysis Intracellular Signaling Peptides and Proteins NF-kappa B Cell Biology Oligonucleotides Antisense Molecular biology Neoplasm Proteins Cell biology Endothelial stem cell Cysteine Endopeptidases medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 chemistry Proteasome Proteasome inhibitor Myeloid Cell Leukemia Sequence 1 Protein Tumor necrosis factor alpha Endothelium Vascular Carrier Proteins Interleukin-1 medicine.drug |
| Zdroj: | Journal of Biological Chemistry. 276:14924-14932 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m100819200 |
| Popis: | Lipopolysaccharide (LPS) has been implicated as the bacterial component responsible for much of the endothelial cell injury/dysfunction associated with Gram-negative bacterial infections. Protein synthesis inhibition is required to sensitize the endothelium to lipopolysaccharide-induced apoptosis, suggesting that a constitutive or inducible cytoprotective protein(s) is required for endothelial survival. We have identified two known endothelial anti-apoptotic proteins, c-FLIP and Mcl-1, the expression of which is decreased markedly in the presence of cycloheximide. Decreased expression of both proteins preceded apoptosis evoked by lipopolysaccharide + cycloheximide. Caspase inhibition protected against apoptosis, but not the decreased expression of c-FLIP and Mcl-1, suggesting that they exert protection upstream of caspase activation. Inhibition of the degradation of these two proteins with the proteasome inhibitor, lactacystin, prevented lipopolysaccharide + cycloheximide-induced apoptosis. Similarly, lactacystin protected against endothelial apoptosis induced by either tumor necrosis factor-alpha or interleukin-1beta in the presence of cycloheximide. That apoptosis could be blocked in the absence of new protein synthesis by inhibition of the proteasome degradative pathway implicates the requisite involvement of a constitutively expressed protein(s) in the endothelial cytoprotective pathway. Finally, reduction of FLIP expression with antisense oligonucleotides sensitized endothelial cells to LPS killing, demonstrating a definitive role for FLIP in the protection of endothelial cells from LPS-induced apoptosis. |
| Databáze: | OpenAIRE |
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