HIV-1 envelope glycoprotein 120 induces cyclooxygenase-2 expression in astrocytoma cells through a nuclear factor-kappaB-dependent mechanism.
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.
Alvarez
Susana
S
Laboratory of Inmuno-Biología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Serramía
Ma Jesús
MJ
Fresno
Manuel
M
Muñoz-Fernández
Ma Angeles
MA
D001254:Astrocytoma / Q000378:metabolism*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D015699:HIV Envelope Protein gp120; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D019718:Receptors, CXCR4; D051546:Cyclooxygenase 2