Interleukin-3 inhibits cycloheximide induction of C-jun mRNA in human monocytes: possible role for a serine/threonine phosphatase.
Cycloheximide is a strong inducer of the c-jun protooncogene mRNA at concentrations (< or = 50 ng/ml) that do not inhibit protein synthesis in human monocytes. This induction is transient lasting 30-60 min in contrast to the sustained induction obtained with concentrations that inhibit protein synthesis. The pluripotent colony stimulating factor interleukin-3 (IL-3) (10 ng/ml) is also a modest inducer of the c-jun gene in these cells; however, in combination with cycloheximide, IL-3 dramatically reduces the c-jun induction below levels induced by cycloheximide alone. This is a true inhibition and is not due to a change in temporal kinetics of induction because the suppression in the presence of IL-3 is observed at both 30 and 60 min after simultaneous addition of both IL-3 and cycloheximide. Preincubation of monocytes with 12.5 nM okadaic acid (a potent inhibitor of protein phosphatases 1 and 2A) and cycloheximide prior to addition of IL-3 restored the level of c-jun induction to that mediated by cycloheximide alone. This concentration of okadaic acid inhibited almost 70% of the phosphorylase phosphatase activity in monocyte lysates. These observations suggest that activation of protein serine/threonine phosphatase(s) underlies the ability of IL-3 to inhibit cycloheximide induction of c-jun in monocytes.
Department of Cell Biology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855.
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D003513:Cycloheximide / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D004988:Ethers, Cyclic / Q000494:pharmacology; D006706:Homeostasis; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology*; D009000:Monocytes / Q000378:metabolism*; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D010765:Phosphorylase Phosphatase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004988:Ethers, Cyclic; D007377:Interleukin-3; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D019319:Okadaic Acid; D003513:Cycloheximide; D010749:Phosphoprotein Phosphatases; D010765:Phosphorylase Phosphatase