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.