INHIBITION OF LEUKOTRIENE PRODUCTION BY FK506 IN RAT BASOPHILIC LEUKEMIA-1 CELLS

We investigated the inhibitory action of FK506 (0.0005-5 mu g/ml) on t he metabolism of arachidonate 5-lipoxygenase in rat basophilic leukemi a-1 cells. Cells were stimulated with A23187 (10(-5) mol/1) for 15 min in the absence or presence of various concentrations of FK506. Arachi donate 5-lipoxygenase metabolites, peptide leukotrienes (LTs), leukotr iene Bq (LTB(4)) and 5-hydroxyeicosatetraenoic acid (5-HETE) were meas ured by high-performance liquid chromatography. FK506 inhibited A23187 -stimulated production of peptide LTs, LTB(4) and 5-HETE in intact cel ls by up to 77, 73 and 60%, respectively. Phospholipase Az activity, m easured by the release of H-3-arachidonic acid (AA), was not significa ntly inhibited by FK506. The synthesis of peptide LTs and LTB(4) was n ot inhibited by FK506 when leukotriene A(4)-free acid was added to the culture medium. The synthesis of peptide LTs, LTB(4) and 5-HETE was n ot affected by FK506 in a eel lysate study using AA as the subtrate. T hese results indicate that FK506 inhibits the production of peptide LT s, LTB(4) and 5-HETE by inhibiting 5-lipoxygenase activity in intact c ells. The inhibition is not a direct action on 5-lipoxygenase but resu lts from the activating processes of this enzyme.