Dexamethasone inhibition of interleukin 1 beta production by human monocytes. Posttranscriptional mechanisms.
Dexamethasone is known to have an inhibitory effect on IL-1 production. To determine the mechanism(s) of this inhibition, adherent human blood monocytes were stimulated with Escherichia coli lipopolysaccharide (LPS) (10 micrograms/ml) in the presence of dexamethasone. Nuclear transcription run-off assays showed that LPS induced IL-1 beta gene transcription two- to fourfold and that this induction was unaffected by dexamethasone exposure (10(-5) M). The lack of dexamethasone's transcriptional effects was further supported by the absence of any significant change in IL-1 beta mRNA accumulation between LPS-stimulated monocytes exposed or unexposed to dexamethasone, as determined by Northern blot analysis. Posttranscriptionally, dexamethasone was found to have multiple effects: slight prolongation of IL-1 beta mRNA half-life, moderate inhibition of translation of the IL-1 beta precursor, and profound inhibition of the release of IL-1 beta into the extracellular fluid. The data indicate that IL-1 beta is first translated as the 33,000-D pro-IL-1 beta protein, the predominant intracellular form, and the processed to a 17,500-D IL-1 beta protein before or during extracellular transport. The major inhibitory effects of dexamethasone appear to be directed at the translational and posttranslational steps involved in these events.
Kern
J A
JA
Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia 19104-4283.
Lamb
R J
RJ
Reed
J C
JC
Daniele
R P
RP
Nowell
P C
PC
D003907:Dexamethasone / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D009000:Monocytes / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
D007375:Interleukin-1; D012333:RNA, Messenger; D003907:Dexamethasone