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

J Neurochem. 2005 Aug;94(3):850-61. doi: 10.1111/j.1471-4159.2005.03267.x. Epub 2005 Jul 7.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anthracenes / pharmacology
  • Antioxidants / pharmacology
  • Blotting, Northern / methods
  • CD4 Antigens / genetics
  • CD4 Antigens / 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
  • Proline / pharmacology
  • Promoter Regions, Genetic / physiology
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Proto-Oncogene Proteins c-jun / metabolism
  • Pyridines / pharmacology
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism
  • Thiocarbamates / pharmacology
  • Time Factors
  • Transcription Factor AP-1 / physiology*
  • Transfection / methods
  • Tumor Necrosis Factor-alpha / pharmacology
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 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