Transcription, translation and secretion of interleukin 1 and tumor necrosis factor: effects of tebufelone, a dual cyclooxygenase/5-lipoxygenase inhibitor

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Abstract
We examined the effect of tebufelone, a dual cyclooxygenase (CO)/5-lipoxygen-ase (LO) inhibitor, on the synthesis, secretion and gene expression of interleukin (IL) 1β and tumor necrosis factor (TNF)-α by human peripheral blood mono-nuclear cells (PBMC). Basal concentrations of immunoreactive IL 1β and TNF-α after 18–24 h, in the absence or presence of tebufelone (≤ 12.5 μM), were near the limit of detection (100 pg/ml). By contrast, preincubation (1 h) of cells, in amounts of tebufelone which decrease the formation of leukotriene (LT) B4, markedly enhanced (up to 500%) the synthesis of IL 1β and TNF-α following lipopolysaccharide (LPS), heat-killed Staphylococcus epidermidis or concanavalin A stimulation. Moreover, a disproportionate amount of the overall increase in IL 1(α and β) was secreted in contrast to the amount which remained cell associated, an effect unrelated to cell damage or leakage as tebufelone had no effect on either lactate dehydrogenase release by PBMC, or mitochondrial dehydrogenases of adherent monocytes as detected by enzymatic cleavage of the substrate 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide. There was no inverse correlation between the changes in prostaglandin (PG)E2 levels and TNF-α or IL 1β synthesis, and when PG formation was maximally inhibited by preincubating the cells in indomethacin, tebufelone, added 1 h before the stimulus, continued to enhance the synthesis of IL 1β although not that of TNF-α. The addition of the CO/5-LO inhibitor 2 h after LPS stimulation, however, did not interfere with IL 1β synthesis, suggesting that tebufelone interacts with an early event(s) in the activation of PBMC. For IL 1β and TNF-α, basal and stimulated (4 h post LPS) mRNA levels were not increased by tebufelone, despite a concomitant increase in the synthesis of IL1β. In conclusion, we have demonstrated that tebufelone enhances IL 1(α and β) and TNF-α synthesis at concentrations which suppress leukotriene formation. These findings argue against a role of 5-LO products as necessary intermediates of IL 1(α and β) and TNF-α synthesis.

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