Cot kinase induces cyclooxygenase-2 expression in T cells through activation of the nuclear factor of activated T cells

Cyclooxygenase-2 (COX-2) is induced in human T lymphocytes upon T cell rece ptor triggering. Here we report that Cot kinase, a mitogen-activated protei n kinase kinase kinase involved in T cell activation, up-regulates COX-2 ge ne expression in Jurkat T cells. Induction of COX-2 promoter activity by Co t kinase occurred mainly through activation of the nuclear factor of activa ted T cells (NFAT). Mutation of the distal (-105/-97) and proximal (-76/-61 ) NEAT response elements in the COX-2 promoter abolished the activation ind uced by Cot kinase. Even more, coexpression of a dominant negative version of NFAT inhibited Cot kinase-mediated COX-2 promoter activation, whereas co transfection of a constitutively active version of the calcium-dependent ph osphatase calcineurin synergizes with Cot kinase in the up-regulation of CO X-2 promoter-driven transcription. Strikingly, Cot kinase increased transac tivation mediated by a GAL4-NFAT fusion protein containing the N-terminal t ransactivation domain of NFATp. In contrast to phorbol ester plus calcium i onophore A23187, Cot kinase increases both COX-2 promoter activity and NFAT -mediated transactivation in a cyclosporin A-independent manner. These data indicate that Cot kinase up-regulates COX-2 promoter-driven transcription through the NFAT response elements, being the Cot kinase-induced NFAT-depen dent transactivation presumably implicated in this up-regulation.