Differential turnover of enzymes involved in human monocyte eicosanoid metabolism. Selective inhibition of cyclooxygenase product formation by cycloheximide in the absence of effects on 5-lipoxygenase or phospholipase A2.
Human monocytes treated with cycloheximide (CHX) demonstrated a concentration- and time-dependent inhibition of prostaglandin E2 (PGE2) synthesis and release in response to stimulation with phorbol myristate acetate, ionomycin, serum-treated zymosan, or concanavalin A. The effect of CHX required preincubation and was largely reversible within 2 hr. Thromboxane A2 release was affected similarly but no comparable effects were observed on labeled arachidonic acid release or leukotriene B4 generation. The PGE2 response was also inhibited by CHX when monocytes were given exogenous arachidonic acid with or without stimulation. CHX pretreatment also comparably decreased the amount of immunoreactive cyclooxygenase in resting and stimulated monocytes. These data indicate that monocyte cyclooxygenase, in contrast to phospholipase A2 or 5-lipoxygenase and their regulatory proteins, turns over rapidly and may be a target for up- or down-regulation by pharmacologic or (potentially) physiologic agents which affect protein synthesis or degradation.
Hoffman
T
T
Laboratory of Cell Biology, U.S. Food and Drug Administration, Bethesda, MD 20892.
Lee
Y L
YL
Lizzio
E F
EF
Tripathi
A K
AK
Bonvini
E
E
Puri
J
J
D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016718:Arachidonic Acid / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D014176:Protein Biosynthesis; D013928:Thromboxane A2 / Q000096:biosynthesis
D016861:Cyclooxygenase Inhibitors; D007975:Leukotriene B4; D016718:Arachidonic Acid; D013928:Thromboxane A2; D003513:Cycloheximide; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone