Abstract
The human CHP100 neuroblastoma cell line has been shown to provide an useful in vitro model to elucidate the mechanisms underlying HIV-1 gp120 neurotoxicity. Here we report western blotting evidence demonstrating that exposure to a cytotoxic concentration of the viral coat protein up-regulates expression of the inducible isoform of cyclooxygenase (COX-2) in neuroblastoma cells and this seems to be due to the previously observed increase in secreted IL-1beta. In fact, here we show that acetyl-Tyr-Val-Ala-Asp-chloromethylketone (Ac-YVAD-CMK) and t-butoxycarbonyl-L-aspartic acid benzyl ester-chloromethylketone (Boc-Asp-(OBzl)-CMK), two inhibitors of Interleukin-1 Converting Enzyme (ICE; also referred to as caspase-1), abolish COX-2 expression enhanced by gp120 and consequent cell death. In addition, NS-398, a selective inhibitor of COX-2 activity, affords neuroprotection strengthening the role of COX-2 in the mechanisms of death. In conclusion, the present data support the notion that IL-1beta is the signal through which gp120 elevates COX-2 expression and the latter is strongly implicated in the mechanisms underlying cytotoxicity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Caspase 1 / metabolism
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Caspase Inhibitors*
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Cell Death
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / pharmacology
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Cysteine Proteinase Inhibitors / pharmacology
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Gene Expression Regulation
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HIV / physiology
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HIV Envelope Protein gp120 / metabolism*
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Humans
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Interleukin-1 / metabolism
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Isoenzymes / metabolism*
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Membrane Proteins
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Neuroblastoma / enzymology*
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Neuroblastoma / pathology
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Neuroblastoma / virology*
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Nitrobenzenes / pharmacology
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Prostaglandin-Endoperoxide Synthases / metabolism*
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Sulfonamides / pharmacology
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Tumor Cells, Cultured
Substances
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Amino Acid Chloromethyl Ketones
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Caspase Inhibitors
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Cysteine Proteinase Inhibitors
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HIV Envelope Protein gp120
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Interleukin-1
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Isoenzymes
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Membrane Proteins
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N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
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N-tert-butyloxycarbonyl-aspartyl (benzyl)chloromethylketone
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Nitrobenzenes
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Sulfonamides
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N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Caspase 1