NF-κB 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 similar to 0.9 and similar to 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. (C) 2003 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.