Dexamethasone Increases Expression of 5‐Lipoxygenase and its Activating Protein in Human Monocytes and THP‐1 Cells

Abstract

The aim of this study was to assess the effect of dexamethasone on 5-lipoxygenase pathway expression in human peripheral blood monocytes and the acute monocytic leukemia cell line, THP-I. Cells were conditioned over a period of days with dexamethasone, at concentrations relevant in vivo, to study the effect of the glucocorticoid on calcium-ionophore-stimulated 5-lipoxygenase product and arachidonic acid release. The effect of dexamethasone on levels of immunoreactive protein and steady-state messenger RNA encoding for 5-lipoxygenase and its activating protein (5-LAP) was also assessed. Dexamethasone increased the stimulated release of 5-lipoxygenase products from both monocytes and THP-1 cells in a dose-dependent fashion. The increase in product generation was not due to changes in the availability of arachidonic acid. However, immunoreactive protein and steady-state messenger RNA encoding for Slipoxygenase and 5-LAP were increased by conditioning with dexamethasone. There was no apparent effect of the glucocorticoid on LTA,-hydrolase-immunoreactive protein levels or specific activity. We conclude that dexamethasone increases 5-lipoxygenase pathway expression in both monocytes and in THP-1 cells. This effect is due, at least in part, to increases in immunoreactive protein and steady-state messenger RNA encoding for 5-lipoxygenase and 5-LAP. These results suggest a role for glucocorticoids in the regulation of 5-lipoxygenase pathway expression in mononuclear phagocytes.Keywords: arachidonic acid; leukotriene ; 5-lipoxygenase ; 5-lipoxygenase-activating protein; glucocorticoid.Leukotrienes are oxygenated metabolites of arachidonic acid derived via the 5-lipoxygenase pathway. They are potent inflammatory mediators and have been implicated in the pathophysiology of a large number of diseases [l]. The enzyme S-lipoxygenase, in association with its activating protein (SLAP), catalyzes the first two steps of the conversion of arachidonic acid to leukotrienes, resulting in the synthesis of the unstable epoxide intermediate, leukotriene A, (LTA,). LTA,, in turn, can subsequently be metabolized to either LTB, or LTC, by the action of LTA, hydrolase and LTC, synthase, respectively [ZJ.5-Lipoxygenase pathway expression appears to be actively regulated. The distribution of component enzymes of the pathway is restricted to a limited number of cell types, i.e. to predominantly those of myeloid origin [3]. Moreover, recent studies have shown modulation of this pathway in vitro Correspondence to T.

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