Human immunodeficiency virus-1 gp120 alters astroglial function, which compromises the function of the nearby of neuronal cells contributing to the cognitive impairment in human immunodeficiency virus-1 infection. Cyclooxygenase (COX)-2 has been involved in this process, although the intracellular pathways and second messengers involved are yet unknown. We have investigated the role of gp120-induced COX-2 in the astrocytoma human cell line U-87, and the different pathways involved in this activation. COX-2 mRNA and protein expression were detected in gp120-stimulated cells. Moreover, gp120 induces COX-2 promoter transcription. The effect of gp120 was abrogated by a neutralizing antibody against the chemokine receptor CXCR4 neutralizing antibody. Analysis of the promoter show that deletion or mutation of a proximal nuclear factor (NF)-kappaB site completely abrogated gp120-dependent transcription. NF-kappaB but neither Activating protein-1 nor nuclear factor of activated T-cells-dependent transcription was induced by gp120, as shown by reporter and electrophoretic mobility shift assays. In addition, transfection assays with the NF-kappaB inhibitor, IkappaBalpha, prevented gp120-mediated COX-2 induction. In contrast, there was no inhibition of COX-2 promoter transcription by expressing a dominant negative c-Jun, or nuclear factor of activated T-cells constructs. The antioxidant pyrrolidine dithiocarbamate inhibited COX-2 protein expression and COX-2 transcriptional activity induced by gp120. Thus, our results indicate that gp120 induced COX-2 transcription through NF-kappaB activation in astrocytoma cells.