An essential role of the nuclear factor of activated T cells in the regulation of the expression of the cyclooxygenase-2 gene in human T lymphocytes

We have previously reported that transcriptional induction of cyclooxygenas e-2 (COX-2) isoenzyme occurs early after T cell receptor triggering, sugges ting functional implications of cyclooxygenase activity in this process. He re, we identify the cis-acting elements responsible for the transcriptional activation of this gene in human T lymphocytes. COX-2 promoter activity wa s induced upon T cell activation both in primary resting T lymphocytes and in Jurkat cells. This induction was abrogated by inhibition of calcineurin phosphatase with the immunosuppressive drug cyclosporin A, whereas expressi on of an active calcineurin catalytic subunit enhanced COX-2 transcriptiona l activation. Moreover, co-transfection of nuclear factor of activated T ce lls (NFAT) wild type protein transactivated COX-2 promoter activity. Conver sely, dominant negative mutants of NFATc or c-Jun proteins inhibited COX-2 induction. Electro phoretic mobility shift assays and site-directed mutagen esis allowed the identification of two regions of DNA located in the positi ons -117 and -58 relative to the transcriptional start site that serves as NEAT recognition sequences. These results emphasize the central role that t he Ca2+/calcineurin pathway plays in COX-2 transcriptional regulation in T lymphocytes pointing to NFAT/activator protein-1 transcription factors as e ssential for COX-2 promoter regulation in these cells.