DEXAMETHASONE DOWN-REGULATES THE 85-KDA PHOSPHOLIPASE A(2) IN MOUSE MACROPHAGES AND SUPPRESSES ITS ACTIVATION

We have studied the effects of dexamethasone (dex) (i) on the level of the arachidonate-mobilizing phospholipase A(2) (PLA(2)-85) in macrophages, (ii) on the stimulus-induced activation of this enzyme, and (iii) on the stimulus-induced release of arachidonate. Treatment of macrophages with 10 nM dex led to progressive reduction of PLA(2)-85 down to approx. 35% of control levels in 20 h in the absence of stimuli. This was accompanied by a partial inhibition of calcium-ionophore-induced arachidonate release. In contrast, the ability of zymosan or phorbol ester to cause both persistent activation of PLA(2)-85 and arachidonate release was greatly reduced or abolished, However, the protein phosphatase inhibitor okadaic acid, previously shown to cause enhanced phosphorylation and persistent activation of PLA(2)-85, was still able to exert this effect on the dex-suppressed PLA(2)-85. This suggests that the effect of okadaic acid was exerted at, or downstream of, the dex-sensitive step(s). Treatment with dex also led to inhibition of the characteristic changes in phosphoprotein labelling induced by phorbol ester or zymosan. However, phorbol-dibutyrate-binding isoforms of protein kinase C were not severely down-regulated. Thus dex was found to down-regulate PLA(2)-85 and, in addition, to affect one or more component(s) in the signal chain that normally leads to its activation. However, okadaic acid retained the ability to cause activation of PLA(2)-85.