(±)-3-[4-(2-dimethylamino-1-methylethoxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-1-acetic acid (Y-25510) stimulates production of IL-1β and IL-6 at the level of messenger RNA expression in cultured human monocytes

Abstract

(±)-3-[4-(2-Dimethylamino-l-methylethoxy)phenyl]-1H-pyrazolo[3, 4-b]pyridine-l-acetic acid (Y-25510) stimulated the mRNA expression for interleukin-lβ (IL-1β), 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-1β mRNA expression by Y-25510 was suppressed by cycloheximide, an inhibitor of protein synthesis. This phenomenon indicates that the stimulation requires de novo protein synthesis. In contrast, the stimulation of mRNA expression for IL-6 by Y-25510 was not suppressed by cycloheximide but suppressed by Nα-p-tosyl-L-phenylalanine chloromethyl ketone (TPCK), an inhibitor of nuclear transcription factor-κB (NF-κB) activation, in the presence of LPS, suggesting that the stimulation requires NF-κ activation. These results demonstrate that Y-25510 stimulates the mRNA expression for IL-1β and IL-6 by different mechanisms. Dexamethasone suppressed the LPS-induced expression of mRNA for IL-1β 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-1β and IL-6 by different mechanisms from those of LPS.