Regulation of RNA and Protein Expression

Barring a few cases, the expression of CD137 and CD137L is activation-induced. CD137 is not detected (<3%) on resting T cells and T cell lines. However, when the T cells are stimulated with a variety of agonists (plate-bound anti-CD3, ConA, PHA, IL-2, IL-4, anti-CD28, PMA, and ionomycin alone or in various combination), in the presence of APCs, it is stably upregulated (Garni-Wagner et al., 1996; Kwon et al, 1987, 1989; Pollok et al, 1993). Using T cell clones, Kim et al. (2003) have shown that CD137 mRNA can be detected within 3 h of stimulation, and CD137 is surface-expressed by 12 h post-stimulation reaching maximal levels by 24 h. Induction is inhibited by cyclosporin A (Kwon et al.,

1989) and cyclohexamide (Kwon et al., 1987), and actinomycin D halved CD137 transcript levels in activated lymphocytes within 30 min, pointing to a relatively short half-life (Schwarz et al., 1995). The fact that CD137 appears late during activation has led to the suggestion that it may be localized to memory T cells (Garni-Wagner et al., 1996). Interestingly, CD137 is also upregulated by DNA damaging agents such as anti-cancer drugs, or y-irradiation, in human PBMC (Kim etal., 2002). Using 5'-deletion constructs of the CD137 promoter inluciferase reporter assays, Kim et al. (2003) demonstrated that the transcriptional elements mediating CD137 upregulation are located between ~0.9 and ~1.1 kb of the translational start site. Further characterization of these sites by electrophoretic mobility shift assays and site-directed mutagenesis revealed that nuclear factor kB (NF-kB) and activating protein-1 (AP-1) are involved. Also, MEK and c-Jun N-terminal kinase-1 are required for activation-dependent CD137 upregulation.

CD137L, on the other hand, is highly expressed on mature B and macrophage cell lines as well as on anti-^-activated B cells and dendritic cells (Pollok et al., 1994). Like CD137, CD137L is inducible in T cells (Goodwin et al., 1993).

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