Inhibition of leukotriene production by FK506 in rat basophilic leukemia-1 cells.
We investigated the inhibitory action of FK506 (0.0005-5 micrograms/ml) on the metabolism of arachidonate 5-lipoxygenase in rat basophilic leukemia-1 cells. Cells were stimulated with A23187 (10(-5) mol/l) for 15 min in the absence or presence of various concentrations of FK506. Arachidonate 5-lipoxygenase metabolites, peptide leukotrienes (LTs), leukotriene B4 (LTB4) and 5-hydroxyeicosatetraenoic acid (5-HETE) were measured by high-performance liquid chromatography. FK506 inhibited A23187-stimulated production of peptide LTs, LTB4 and 5-HETE in intact cells by up to 77, 73 and 60%, respectively. Phospholipase A2 activity, measured by the release of 3H-arachidonic acid (AA), was not significantly inhibited by FK506. The synthesis of peptide LTs and LTB4 was not inhibited by FK506 when leukotriene A4-free acid was added to the culture medium. The synthesis of peptide LTs, LTB4 and 5-HETE was not affected by FK506 in a cell lysate study using AA as the substrate. These results indicate that FK506 inhibits the production of peptide LTs, LTB4 and 5-HETE by inhibiting 5-lipoxygenase activity in intact cells. The inhibition is not a direct action on 5-lipoxygenase but results from the activating processes of this enzyme.
Hamasaki
Y
Y
Department of Pediatrics, Saga Medical School, Japan.
Kobayashi
I
I
Matsumoto
S
S
Zaitu
M
M
Muro
E
E
Ichimaru
T
T
Miyazaki
S
S
D000818:Animals; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D015471:Leukemia, Basophilic, Acute; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D051381:Rats; D016559:Tacrolimus / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D006893:Hydroxyeicosatetraenoic Acids; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D010741:Phospholipases A; D054467:Phospholipases A2; D016559:Tacrolimus