Extracellular HIV-Tat induces cyclooxygenase-2 in glial cells through activation of nuclear factor of activated T cells.
Both the HIV-1 protein Tat and cyclooxygenase-2 (COX-2) have been involved in the neuropathogenesis associated with HIV-1 infection. However, the relationship among them has not been addressed. Here, we found that extracellular Tat was able to induce COX-2 mRNA and protein expression and PGE2 synthesis in astrocytoma cell lines and primary human astrocytes. Moreover, Tat induced COX-2 promoter transcription. Deletion of NF-kappaB sites of the promoter did not diminish Tat-dependent transcription. Interestingly, Tat did not induce NF-kappaB activity, suggesting that NF-kappaB was not necessary to control COX-2 transcription induced by Tat. In contrast, deletion or mutation of the NFAT and/or AP-1 site abrogated COX-2 induction by Tat. Moreover, Tat induced transcription of NFAT- and AP-1-dependent reporter genes. Transfection of a dominant negative c-Jun mutant protein, TAM-67, or of a dominant negative version of NFAT, efficiently blocked the induction of COX-2 promoter by Tat, confirming the requirement of both transcription factors. Moreover, Tat induced NFAT translocation to the nucleus and binding to the distal site of the COX-2 promoter. The importance of NFAT and AP-1 in COX-2 induction and PGE2 synthesis by Tat was corroborated by using pharmacological inhibitors of the NFAlphaTau, ERK, and JNK pathways. In summary, our results indicate that HIV-1 Tat was able to induce COX-2 and PGE2 synthesis in astrocytic cells through an NFAT/AP-1-dependent mechanism.
Blanco
Almudena
A
Laboratorio Inmuno-Biología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Alvarez
Susana
S
Fresno
Manuel
M
Muñoz-Fernández
María Angeles
MA
D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D005786:Gene Expression Regulation; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism / Q000821:virology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism* / Q000494:pharmacology
D016328:NF-kappa B; D050778:NFATC Transcription Factors; D018808:Transcription Factor AP-1; D054322:tat Gene Products, Human Immunodeficiency Virus; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone