Human immunodeficiency virus type 1 envelope glycoprotein 120 induces cyclooxygenase-2 expression in neuroblastoma cells through a nuclear factor-kappaB and activating protein-1 mediated mechanism.

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.

• Authors: Susana Alvarez, M Jesús Serramía, Manuel Fresno, Mángeles Muñoz-Fernández
• Journal: Journal of neurochemistry (J Neurochem) Vol. 94 Issue 3 Pg. 850-61 (Aug 2005) ISSN: 0022-3042 [Print] England
• PMID: 16001969 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracenes
• Antioxidants
• CD4 Antigens
• CXCL12 protein, human
• Chemokine CCL5
• Chemokine CXCL12
• Chemokines, CXC
• Enzyme Inhibitors
• HIV Envelope Protein gp120
• Imidazoles
• Interleukin-1
• Membrane Proteins
• NF-kappa B
• Proto-Oncogene Proteins c-jun
• Pyridines
• Receptors, CCR5
• Receptors, CXCR4
• Thiocarbamates
• Transcription Factor AP-1
• Tumor Necrosis Factor-alpha
• prolinedithiocarbamate
• pyrazolanthrone
• Proline
• Luciferases
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• SB 203580

Topics

• Anthracenes (pharmacology)
• Antioxidants (pharmacology)
• Blotting, Northern (methods)
• CD4 Antigens (genetics, metabolism)
• Cell Line, Tumor
• Chemokine CCL5 (metabolism)
• Chemokine CXCL12
• Chemokines, CXC (pharmacology)
• Cyclooxygenase 2
• Drug Interactions
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Gene Expression (drug effects)
• HIV Envelope Protein gp120 (pharmacology)
• Humans
• Imidazoles (pharmacology)
• Interleukin-1 (pharmacology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Luciferases (metabolism)
• Membrane Proteins
• Mutagenesis (physiology)
• NF-kappa B (metabolism)
• Neuroblastoma (metabolism)
• Proline (analogs & derivatives, pharmacology)
• Promoter Regions, Genetic (physiology)
• Prostaglandin-Endoperoxide Synthases (genetics, metabolism)
• Proto-Oncogene Proteins c-jun (metabolism)
• Pyridines (pharmacology)
• Receptors, CCR5 (genetics, metabolism)
• Receptors, CXCR4 (genetics, metabolism)
• Thiocarbamates (pharmacology)
• Time Factors
• Transcription Factor AP-1 (physiology)
• Transfection (methods)
• Tumor Necrosis Factor-alpha (pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)