Inhibition of Leukotriene Production by FK506 in Rat Basophilic Leukemia-1 Cells

Abstract

We investigated the inhibitory action of FK506 (0.0005-5 µg/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-stim-ulated 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-achidonic 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 subtrate. 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.

Inhibition of Arachidonic Acid Release by Cytosolic Phospholipase A2 Is Involved in the Antiapoptotic Effect of FK506 and Cyclosporin A on Astrocytes Exposed to Simulated Ischemia In Vitro

“…Furthermore, limited effects of FK506 on AA release and cPLA 2 activity reported in the present study are in agreement with previously published results of studies performed on cell types other than astrocytes (69,70). …”

Pharmacological Neuroprotection for Acute Spinal Cord Injury

“…FK-506 exerts neuroprotection through calcineurin-independent mechanisms such as lowered production of leukotrienes and arachidonic acid [77,78] and heat shock protein upregulation [79,80]. Studies have shown that FK-506 reduces lipid peroxidation, COX-2 activity, and caspase-3 activation [81,82].…”

Pharmacological Neuroprotective Therapy for Acute Spinal Cord Injury: State of the Art

“…FK506 could also exert calcineurin-independent actions such as leukotriene and arachidonic acid inhibition [72][73][74] or heat shock proteins up-regulation [75,76]. FK506 could also exert calcineurin-independent actions such as leukotriene and arachidonic acid inhibition [72][73][74] or heat shock proteins up-regulation [75,76].…”