Dexamethasone down-regulates the 85 kDa phospholipase A2 in mouse macrophages and suppresses its activation.
We have studied the effects of dexamethasone (dex) (i) on the level of the arachidonate-mobilizing phospholipase A2 (PLA2-85) 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 PLA2-85 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 PLA2-85 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 PLA2-85, was still able to exert this effect on the dex-suppressed PLA2-85. 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 PLA2-85 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 PLA2-85.
Gewert
K
K
Department of Medical and Physiological Chemistry, Lund University, Sweden.
Sundler
R
R
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D010766:Phosphorylation
D016718:Arachidonic Acid; D003907:Dexamethasone; D010741:Phospholipases A; D054467:Phospholipases A2