Dexamethasone inhibition of interleukin 1 beta production by human monocytes. Posttranscriptional mechanisms

Abstract

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 μg/ml) in the presence of dexamethasone. Nuclear transcription run-off assays showed that LPS induced IL-1β 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 absence of any significant change in IL-1β 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-1β mRNA half-life, moderate inhibition of translation of the IL-1β precursor, and profound inhibition of the release of IL-1β into the extracellular fluid. The data indicate that IL-1β is first translated as the 33,000-D pro-IL-1β protein, the predominant intracellular form, and the processed to a 17,500-D IL-1β 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.