(+/-)-3-[4-(2-dimethylamino-1-methylethoxy)-phenyl]-1H-pyrazolo[3,4- B]pyridine-1-acetic acid (Y-25510) stimulates production of IL-1 beta and IL-6 at the level of messenger RNA expression in cultured human monocytes.
(+/-)-3-[4-(2-Dimethylamino-1-methylethoxy)phenyl]-1H-pyrazolo[3, 4-b]pyridine-1-acetic acid (Y-25510) stimulated the mRNA expression for interleukin-1 beta (IL-1 beta), and enhanced the expression induced by lipopolysaccharide (LPS) in cultured human peripheral blood mononuclear cells (PBMC) and THP-1 cells, a cell-line derived from human monocytic leukemia. Y-25510 also stimulated the mRNA expression for IL-6 in both types of the cells, however, the stimulation required the presence of LPS. In THP-1 cells, the stimulation of IL-1 beta mRNA expression by Y-25510 was suppressed by cycloheximide, an inhibitor of protein synthesis. This phenomenon indicates that the stimulation requires de norv protein synthesis. In contrast, the stimulation of mRNA expression for IL-6 by Y-25510 was not suppressed by cycloheximide but suppressed by N alpha-p-tosyl-L-phenylalanine chloromethyl ketone (TPCK), an inhibitor of nuclear transcription factor-kappa B (NF-kappa B) activation, in the presence of LPS, suggesting that the stimulation requires NF-kappa activation. These results demonstrate that Y-25510 stimulates the mRNA expression for IL-1 beta and IL-6 by different mechanisms. Dexamethasone suppressed the LPS-induced expression of mRNA for IL-1 beta and IL-6 in THP-1 cells, whereas the drug never suppressed the mRNA expression for these cytokines in the presence of Y-25510. The result indicates that Y-25510 stimulates the mRNA expression for IL-1 beta and IL-6 by different mechanisms from those of LPS.
Kusuhara
H
H
Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd, Fukuoka, Japan.
Komatsu
H
H
Hisadome
M
M
Ikeda
Y
Y
D003470:Culture Media / Q000378:metabolism / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D003470:Culture Media; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; C078528:Y 25510; D014108:Tosylphenylalanyl Chloromethyl Ketone; D003907:Dexamethasone; D003513:Cycloheximide