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-alpha production is specific to cell type and to inducer, i.e., (i) the compounds enhance TPA-induced TNF-alpha production by human leukemia HL-60 cells, while they inhibit TPA-induced TNF-alpha production by another human leukemia cell line, THP-1, and (ii) the compounds inhibit TNF-alpha 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)-alpha-methylthalidomides, show distinct bidirectional regulatory effects on TNF-alpha production, i.e., only the (S)-form shows TNF-alpha production-enhancing activity in the TPA/HL-60 assay system, while the (R)-form shows much more potent TNF-alpha production-inhibiting activity than the (S)-form in the other assay systems.
Miyachi
H
H
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Azuma
A
A
Hioki
E
E
Iwasaki
S
S
Kobayashi
Y
Y
Hashimoto
Y
Y
D018922:HL-60 Cells; D006801:Humans; D010797:Phthalimides / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013792:Thalidomide / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D010797:Phthalimides; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide