(+ THOXY)-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/

imethylamino-1-methylethoxy)phenyl]-1H-pyrazolo[3, 4]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-255 10 also stimulated the mRNA expression for IL-6 in both types of the c ells, however, the stimulation required the presence of LPS. In THP-1 cells, the stimulation of IL-1 beta mRNA expression by Y-25510 was sup pressed by cycloheximide, an inhibitor of protein synthesis. This phen omenon indicates that the stimulation requires de novo protein synthes is. In contrast, the stimulation of mRNA expression for IL-6 by Y-2551 0 was not suppressed by cycloheximide but suppressed by N alpha-p-tosy l-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 suppress ed 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-255 10 stimulates the mRNA expression for IL-1 beta and IL-6 by different mechanisms from those of LPS. (C) 1997 International Society for Immun opharmacology.