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

• Published in: Journal of neurochemistry 2005-08, Vol.94 (3), p.850
• Main Authors: Álvarez, Susana, Ma Jesús Serramía, Fresno, Manuel, Muñoz-Fernández, MaÁngeles
• Format: Article
• Language: English
• Subjects: Brain; Cells; Cytokines; Dementia; Gene expression; HIV; Human immunodeficiency virus; Proteins
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03267.x

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-[kappa]B (NF-[kappa]B) site abrogated gp120-dependent transcription. More importantly, overexpression of NF-[kappa]B inhibitory subunit, I[kappa]B[alpha], completely abrogated gp120-induced COX-2 activity. However, transfection of p65/relA NF-[kappa]B was not enough to induce COX-2 transcription, suggesting that NF-[kappa]B was necessary but not sufficient to control COX-2 transcription induced by gp120. In addition to NF-[kappa]B, 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-[kappa]B and AP-1 in COX-2 promoter and protein induction was corroborated by using pharmacological NF-[kappa]B, p38 and JNK inhibitors.[PUBLICATION ABSTRACT]