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* Laboratorio Inmuno-Biología Molecular, Hospital General Universitario Gregorio Marañón, and
Centro de Biología Molecular, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain
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-
B sites of the promoter did not diminish Tat-dependent transcription. Interestingly, Tat did not induce NF-B activity, suggesting that NF-B 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 NFAT, 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by grants from Fondos de Investigación Sanitaria (PI061479), Red Temática de Investigación Cooperativa Sanitaria ISCIII (RD06/0006/0035), Fundación para la Investigación y Prevención del SIDA en España (36514/05 and 36536/05), and Fundación Caja Navarra (to M.A.M.F.); from Red Temática de Investigación Cooperativa Sanitaria ISCIII (RED RICET RD06/0021/0016), Programa Nacional de Salud of Spain (SAF 2004-05109 and SAF2005-02220), Laboratorios del Dr. Esteve, the 6th EU Framework Programme European Commission (Integrated Project EICOSANOX, LSH-CT-2004-005033, and MAIN network of excellence), and the Fundación Ramón Areces (to M.F.); and from Fondo de Investigación Sanitaria (PI040883) and Comunidad Autónoma de Madrid (SAL/2001/2004) (to M.A.M.F and M.F.). S.Á. is supported by a fellowship of Fondos de Investigación Sanitaria (CD06/00321), and A.B. is supported by a fellowship of Red Temática de Investigación Cooperativa Sanitaria (RD06/0006/0035).
2 Address correspondence and reprint requests to Dr. María Ángeles Muñoz Fernández, Hospital Gregorio Maranon, Dr. Esquerdo 46, 28007 Madrid, Spain. E-mail address: mmunoz.hgugm{at}salud.madrid.org
3 Abbreviations used in this paper: HAD, HIV-1-associated dementia; HAART, highly active antiretroviral therapy; COX-2, cyclooxygenase-2; Cn, calcineurin; CsA, cyclosporin A; NHA, normal human astrocyte; LTR, long terminal repeat; PTx, pertussis toxin.
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