NF-kappaB and AP-1 regulate activation-dependent CD137 (4-1BB) expression in T cells

4-1BB(CD137) is a member of the tumor necrosis factor receptor superfamily and provides a costimulatory signal by interaction with 4-1BB ligand expressed on antigen-presenting cells. The expression of 4-1BB is known to be activation-dependent. Here, we investigated the transcriptional machinery required for T cell receptor (TCR) activation-dependent induction of 4-1BB expression in CD3-CEM cells treated with phorbol myristate acetate and ionomycin. Using 5'-deletion constructs of 4-1BB promoter in luciferase reporter assays, we demonstrated that the transcriptional elements mediating 4-1BB upregulation were located in the region between approximately 0.9 and approximately 1.1 kb from the translational start site. Characterization of these sites by electrophoretic mobility shift assay and site-directed mutagenesis revealed that nuclear factor kappaB (NF-kappaB) and activating protein-1 (AP-1) are involved. MEK and c-Jun N-terminal kinase-1 activity was required for activation-dependent 4-1BB upregulation. Thus, NF-kappaB and AP-1 are involved in the TCR stimulation-dependent transcriptional regulation of the 4-1BB promoter.