Cell type-/inducer-specific bidirectional regulation by thalidomide and phenylphthalimides of tumor necrosis factor-alpha production and its enantio-dependence

Regulation by thalidomide and phenylphthalimide analogs (FPP-33 and PPS-33) of TNF-α production is specific to cell type and to inducer, i.e., (i) the compounds enhance TPA-induced TNF-α production by human leukemia HL-60 cells, while they inhibit TPA-induced TNF-α production by another human leukemia cell line, THP-1, and (ii) the compounds inhibit TNF-α production by both HL-60 and THP-1 cells when the cells are stimulated with okadaic acid (OA). The structure-activity relationships of these compounds are similar in the four assay systems (TPA/HL-60, TPA/THP-1, OA/HL-60, and OA/THP-1). However, optically active analogs, (S)- and (R)-α-methylthalidomides, show distinct bidirectional regulatory effects on TNF-α production, i.e., only the (S)-form shows TNF-α production-enhancing activity in the TPA/HL-60 assay system, while the (R)-form shows much more potent TNF-α production-inhibiting activity than the (S)-form in the other assay systems.