M. Watanabe et al., ENHANCEMENT BY CYCLOOXYGENASE INHIBITORS OF PLATELET-ACTIVATING-FACTOR PRODUCTION IN THAPSIGARGIN-STIMULATED MACROPHAGES, British Journal of Pharmacology, 116(3), 1995, pp. 2141-2147
1 Thapsigargin stimulated the accumulation of cell-associated platelet
-activating factor (PAF) and extracellular prostaglandin E(2) (PGE(2))
in rat peritoneal macrophages. PAF in the conditioned medium was less
than the detectable amount. To obtain further insight into the mechan
ism of PAF accumulation, the role of PGE(2) in PAF accumulation was in
vestigated. 2 When macrophages were incubated in medium containing tha
psigargin (30 ng ml(-1), 46.1 nM) and cyclo-oxygenase inhibitors such
as indomethacin, naproxen or ibuprofen, the PAF content of the cells a
t 10 min was increased in a concentration-dependent manner in accordan
ce with inhibition of PGE(2) production. The stimulation of PAF accumu
lation by cyclo-oxygenase inhibitors was significant at 10 min. Withou
t stimulation by thapsigargin, cyclo-oxygenase inhibitors did not incr
ease PAF accumulation. 3 In thapsigargin-stimulated macrophages, when
PGE(2) (10(-7) M) was added to the medium, the cyclo-oxygenase inhibit
or-induced stimulation of PAF accumulation at 10 min was markedly inhi
bited. 4 The accumulation of PAF induced by thapsigargin alone at 10 m
in was also inhibited by exogenous PGE(2) (10(-8) and 10(-7) M), or ar
achidonic acid (10(-6) and 10(-5) M) in accordance with the increase i
n PGE(2) production. 5 The accumulation of PAF induced by thapsigargin
alone or by thapsigargin and indomethacin (10(-6) M) was inhibited by
dibutyryl cyclic AMP. 6 These results indicate that the concurrently
produced PGE(2) in thapsigargin-stimulated macrophages down-regulates
PAF accumulation by increasing intracellular cyclic AMP levels, and th
at cyclo-oxygenase inhibitors increase PAF accumulation by inhibiting
PGE(2) production.