Caspase-1 inhibitors abolish deleterious enhancement of COX-2 expression induced by HIV-1 gp120 in human neuroblastoma cells.
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.
Corasaniti
M T
MT
Department of Pharmacobiological Sciences, University 'Magna Graecia' of Catanzaro, Faculty of Pharmacy, C/o Complesso 'Nini; Barbieri', 88021 Roccelletta di Borgia (CZ), Catanzaro, Italy. mtcorasa@unicz.it
Bellizzi
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C
Russo
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Colica
C
C
Amantea
D
D
Di Renzo
G
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D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D020170:Caspase 1 / Q000378:metabolism; D061945:Caspase Inhibitors; D016923:Cell Death; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006678:HIV / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology / Q000821:virology*; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D015699:HIV Envelope Protein gp120; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; C097543:N-tert-butyloxycarbonyl-aspartyl (benzyl)chloromethylketone; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020170:Caspase 1