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J Biol Chem, Vol. 273, Issue 52, 35326-35331, December 25, 1998

Down-regulation of Human Granzyme B Expression by Glucocorticoids
DEXAMETHASONE INHIBITS BINDING TO THE Ikaros AND AP-1 REGULATORY ELEMENTS OF THE GRANZYME B PROMOTER

Alain Wargnier^§, Clotilde Lafaurie^§, Sabine Legros-Maïda^§, Jean-François Bourge^§, François Sigaux^§, Marilyne Sasportes^§, and Pascale Paul

From ^§ INSERM U462, Institut d'Hématologie and  Service de Recherches en Hemato Immunologie-CEA, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France

The serine protease granzyme B is an essential component of the granule exocytosis pathway, a major apoptotic mechanism used by cytotoxic T lymphocytes and natural killer cells to induce target cell apoptosis. Granzyme B gene transcription is induced in activated lymphocytes upon antigenic stimulation, and several regulatory regions including CBF, AP-1, and Ikaros binding sites have been shown to be essential in the control of granzyme B promoter activation. Dexamethasone, a glucocorticoid that is widely used as an immunomodulatory and anti-inflammatory agent, inhibits granzyme B mRNA transcript in phytohemagglutinin-activated peripheral blood mononuclear cells. Transfection of a reporter construct containing the 148 to +60 region of the human granzyme B promoter demonstrated that this region was the target for dexamethasone repression. Mutation of Ikaros or AP-1 binding sites in the context of the granzyme B promoter demonstrated that both sites participate in dexamethasone-mediated inhibition of the granzyme B promoter activity. Electromobility shift assay revealed that dexamethasone abolished the binding of nuclear transcription factors to the Ikaros binding site and reduced AP-1 binding activity. These results indicate that dexamethasone is able to abrogate the transcriptional activity of the human granzyme B gene promoter by inhibiting the binding of nuclear factors at the AP-1 and Ikaros sites.

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