Regulation of interleukin-1 beta production by glucocorticoids in human monocytes: the mechanism of action depends on the activation signal.
Glucocorticoids are known to downregulate interleukin-1 beta production in monocytic cells by two different mechanims: direct inhibition of the gene transcription and destabilization of the preformed interleukin-1 beta mRNA. Now we have examined the effect of the nature of the monocyte activating signal on these two inhibitory mechanims. When human monocytes were preincubated with dexamethasone for 1 hour and then stimulated either with bacterial lipopolysaccharide or phorbol myristate, it was found that dexamethasone inhibited the lipopolysaccharide-induced interleukin-1 beta protein production, but the phorbol myristate-induced production was increased 3-10 fold. This difference was also seen at the mRNA level. When dexamethasone was added to the cultures 3 hours after the stimulators, it clearly decreased the interleukin-1 beta mRNA levels regardless of the stimulator used (although the effect was clearly weaker on the PMA-induced mRNA). Thus these data suggest that the phorbol myristate-induced signal (prolonged protein kinase C activation?) cannot be inhibited by prior incubation with dexamethasone and it also protects the induced mRNA for the degradative action of dexamethasone.
Hurme
M
M
Department of Bacteriology and Immunology, University of Helsinki, Finland.
Siljander
P
P
Anttila
H
H
D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics*; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D013755:Tetradecanoylphorbol Acetate