Abstract
Induction of cyclooxygenase-2 (COX-2) in the brain of people infected with human immunodeficiency virus type 1 (HIV-1) has been proposed as a cause of cognitive impairment in AIDS dementia. Here, we have analyzed the molecular mechanism by which its induction takes place in neuroblastoma cells. The HIV-1 envelope protein gp120 was able to induce COX-2 mRNA and protein in several human neuroblastoma cell lines, which express CXCR4 and CCR5 but not CD4. Moreover, gp120 induces COX-2 promoter transcription. Sequential deletions of the promoter show that deletion of a distal nuclear factor-kappaB (NF-kappaB) site abrogated gp120-dependent transcription. More importantly, overexpression of NF-kappaB inhibitory subunit, IkappaBalpha, completely abrogated gp120-induced COX-2 activity. However, transfection of p65/relA NF-kappaB was not enough to induce COX-2 transcription, suggesting that NF-kappaB was necessary but not sufficient to control COX-2 transcription induced by gp120. In addition to NF-kappaB, activating protein-1 (AP-1) but not nuclear factor of activated T cells (NFAT)-dependent transcription was induced by gp120. Transfection of a dominant negative mutant c-Jun protein, TAM-67, efficiently blocked the induction of COX-2 promoter by gp120, confirming AP-1 requirement. Moreover, gp120 rapidly activates the c-Jun amino-terminal kinase (JNK) and p38 mitogen-activated protein kinase phosphorylation. The importance of NF-kappaB and AP-1 in COX-2 promoter and protein induction was corroborated by using pharmacological NF-kappaB, p38 and JNK inhibitors.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Anthracenes / pharmacology
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Antioxidants / pharmacology
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Blotting, Northern / methods
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CD4 Antigens / genetics
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CD4 Antigens / metabolism
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Cell Line, Tumor
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Chemokine CCL5 / metabolism
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Chemokine CXCL12
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Chemokines, CXC / pharmacology
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Cyclooxygenase 2
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Drug Interactions
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Gene Expression / drug effects*
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HIV Envelope Protein gp120 / pharmacology*
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Humans
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Imidazoles / pharmacology
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Interleukin-1 / pharmacology
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JNK Mitogen-Activated Protein Kinases / metabolism
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Luciferases / metabolism
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Membrane Proteins
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Mutagenesis / physiology
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NF-kappa B / metabolism*
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Neuroblastoma / metabolism
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Proline / analogs & derivatives
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Proline / pharmacology
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Promoter Regions, Genetic / physiology
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism*
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Proto-Oncogene Proteins c-jun / metabolism
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Pyridines / pharmacology
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Receptors, CCR5 / genetics
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Receptors, CCR5 / metabolism
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Receptors, CXCR4 / genetics
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Receptors, CXCR4 / metabolism
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Thiocarbamates / pharmacology
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Time Factors
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Transcription Factor AP-1 / physiology*
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Transfection / methods
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Tumor Necrosis Factor-alpha / pharmacology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Anthracenes
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Antioxidants
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CD4 Antigens
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CXCL12 protein, human
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Chemokine CCL5
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Chemokine CXCL12
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Chemokines, CXC
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Enzyme Inhibitors
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HIV Envelope Protein gp120
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Imidazoles
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Interleukin-1
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Membrane Proteins
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NF-kappa B
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Proto-Oncogene Proteins c-jun
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Pyridines
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Receptors, CCR5
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Receptors, CXCR4
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Thiocarbamates
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Transcription Factor AP-1
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Tumor Necrosis Factor-alpha
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prolinedithiocarbamate
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pyrazolanthrone
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Proline
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Luciferases
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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JNK Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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SB 203580