Endothelial cell death induced by tumor necrosis factor-alpha is inhibited by the Bcl-2 family member, A1.
Endothelial cells play a central role in the inflammatory process. Tumor necrosis factor-alpha (TNF) is a multifunctional cytokine which elicits many of the inflammatory responses of endothelial cells. While TNF directly causes apoptosis of tumor cells and virally infected cells, normal cells are generally resistant. However, most resistant cells, including human endothelial cells, can be rendered susceptible to TNF by inhibiting RNA or protein synthesis. This finding suggests that TNF provides a cell survival signal in addition to a death signal. We have previously cloned a human Bcl-2 homologue, A1, and shown that it is specifically induced by proinflammatory cytokines but not by endothelial growth factors. In this study, we show that retroviral-mediated transfer of the A1 cDNA to a human microvascular endothelial cell line provides protection against cell death initiated by TNF in the presence of actinomycin D. The induction of A1 by TNF in this system is mediated via a protein kinase C pathway. Since TNF signaling has also been shown to proceed via ceramides, we tested whether exogenous ceramides could induce A1. Our findings indicate that ceramides do not induce A1 but do up-regulate c-jun and induce endothelial death. Ceramide-activated endothelial death is also inhibited by A1, suggesting that TNF may initiate divergent survival and death pathways via separate lipid second messengers.
Division of Hematology, University of Washington, Seattle, Washington 98195, USA. karsan@u.washington.edu
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Karsan
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Yee
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Harlan
D017209:Apoptosis; D001483:Base Sequence; D002460:Cell Line; D002518:Ceramides / Q000494:pharmacology; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D003609:Dactinomycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D018398:Homeodomain Proteins; D006801:Humans; D008833:Microcirculation; D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides; D010455:Peptides; D016133:Polymerase Chain Reaction; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D051818:Replication Protein C; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051020:bcl-X Protein
C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human; D002518:Ceramides; D017931:DNA Primers; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C096063:MATA1 protein, S cerevisiae; D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides; D010455:Peptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016755:Proto-Oncogene Proteins c-jun; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D003609:Dactinomycin; C085706:FLAG peptide; D011493:Protein Kinase C; D051818:Replication Protein C; D013755:Tetradecanoylphorbol Acetate