[Novel biological response modifiers: phthalimides with TNF-alpha production regulating activity].
Tumor necrosis factor alpha (TNF-alpha), an important cytokine produced mainly by activated macrophages, plays a critical role in certain physiological immune systems. But it causes severe damage to the host when produced in excess. Therefore, TNF-alpha can be regarded to possess both favorable and unfavorable effects. These pleiotropic effects indicated that TNF-alpha production-enhancers in some cases and TNF-alpha production-inhibitors in other cases would be useful as biological response modifiers (BRMs) under various circumstances. A possible lead compound is thalidomide, which had been used as a hypnotic/sedative agents but was withdrawn from the market because of it's teratogenicity. Thalidomide is a specific inhibitor of TNF-alpha production, and this effect has been shown to be useful for the treatment of various immunodiseases. Recently, we found that the regulation of TNF-alpha production by thalidomide and related hthalimides was both inducer-specific and cell-type-specific, i.e., (I) the compounds enhance 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced TNF-alpha production by 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 both by HL-60 and THP-1 cells when the cells are stimulated with okadaic acid. We also found that in a optically active phthalimide analogues of thalidomide the inducer specific bi-directional regulation of TNF-alpha production is separated. This implies that the target molecule(s) of the two systems are different each other.
Miyachi
H
H
Institute of Molecular and Cellular Biosciences, University of Tokyo, Japan.
Azuma
A
A
Hashimoto
Y
Y
D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D010797:Phthalimides / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013792:Thalidomide / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000502:physiology
D006993:Hypnotics and Sedatives; D007155:Immunologic Factors; D010797:Phthalimides; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide