Cot Kinase Induces Cyclooxygenase-2 Expression in T Cells through Activation of the Nuclear Factor of Activated T Cells

Abstract

Cyclooxygenase-2 (COX-2) is induced in human T lymphocytes upon T cell receptor triggering. Here we report that Cot kinase, a mitogen-activated protein kinase kinase kinase involved in T cell activation, up-regulates COX-2 gene expression in Jurkat T cells. Induction of COX-2 promoter activity by Cot kinase occurred mainly through activation of the nuclear factor of activated T cells (NFAT). Mutation of the distal (-105/-97) and proximal (-76/-61) NFAT response elements in the COX-2 promoter abolished the activation induced by Cot kinase. Even more, coexpression of a dominant negative version of NFAT inhibited Cot kinase-mediated COX-2 promoter activation, whereas cotransfection of a constitutively active version of the calcium-dependent phosphatase calcineurin synergizes with Cot kinase in the up-regulation of COX-2 promoter-driven transcription. Strikingly, Cot kinase increased transactivation mediated by a GAL4-NFAT fusion protein containing the N-terminal transactivation domain of NFATp. In contrast to phorbol ester plus calcium ionophore 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-dependent transactivation presumably implicated in this up-regulation.