Y. Hamasaki et al., CYCLOSPORINE-A INHIBITS LEUKOTRIENE PRODUCTION IN INTACT RBL-1 CELLS WITHOUT INHIBITING LEUKOTRIENE BIOSYNTHETIC-ENZYMES, Prostaglandins, leukotrienes and essential fatty acids, 52(6), 1995, pp. 365-371
The effects of cyclosporin A (CSA) on arachidonic acid (AA) metabolism
were investigated in intact rat basophilic leukemia-1 (RBL-1) cells a
nd cell lysates, Calcium ionophore (A23187)-stimulated synthesis of cy
steinyl leukotrienes (LTC(4), LTD(4), and LTE(4)), LTB(4), and 5-hydro
xyeicosatetraenoic acid (5-HETE) in intact cells in the absence or pre
sence of CSA was measured by reversed-phase high-performance liquid ch
romatography (HPLC). CSA inhibited the production of cysteinyl LTs, LT
B(4), and 5-HETE in intact cells in a dose-dependent manner. The synth
esis of cysteinyl LTs, LTB(4), and 5-HETE was also measured after the
incubation of cell lysates with free AA in the absence or presence of
CSA. CSA did not inhibit synthesis of cysteinyl LTs, but rather stimul
ated production of LTB, and 5-HETE in cell lysate, A23187-stimulated r
elease of incorporated [H-3]AA from intact cells was not inhibited by
CSA. CSA did not inhibit the synthesis of cysteinyl LTs and LTB(4) whe
n cells incubated with LTA(4) as the substrate. These results indicate
that the inhibitory effects of CSA on the synthesis of LTs and 5-HETE
in intact cells are attributable to a modulatory action on a step in
the series of intracellular events that includes the activation of 5-l
ipoxygenase, which are initiated by Ca2(+) influx and end in the relea
se of metabolites from the cell membrane, rather than to a direct inhi
bitory action on enzymes in the LT biosynthetic pathway.