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 sg/ml) in the presence of dexamethasone. Nuclear transcription run-off assays showed that LPS induced IL-1IB 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-I1f 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-1jf mRNA half-life, moderate inhibition of translation of the IHAlfl precursor, and profound inhibition of the release of IL-igi into the extracellular fluid.The data indicate that IL-1fi is first translated as the 33,000-D pro-IL-1ft protein, the predominant intracellular form, and the processed to a 17,500-D IL-i1f 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.

Dexamethasone regulation of the expression of cytokine mRNAs induced by interleukin‐1 in the astrocytoma cell line U373MG

“…We also observed a dexamethasone dose-dependent decrease in the level of BSF-2 and IL-lfl mRNAs induction by rIL-lfl (not shown). Therefore glucocorticoids may inhibit not only mitogen or LPS induced production of cytokines shown in several reports [21][22][23][24][25][26][27][28][29], but also the production of cytokines induced by IL-l.…”

“…Glucocorticoids, the immunosuppressive and anti-inflammatory agents, have been shown to decrease mitogen induced production of IL-2 [21], IL-3 [22] or GM-CSF [22,23], and also production of IL-1 by lipopolysaccharide (LPS) [24][25][26][27][28] or phorbol ester [29].…”

Endogenous cortisol determines the circadian rhythm of lipopolysaccharide‐ but not lipoteichoic acid‐inducible cytokine release

“…in the lM range [6]. Several in vitro studies have investigated the molecular mechanisms underlying these actions, most of them using high concentrations (lM) of the synthetic glucocorticoid dexamethasone [7][8][9][10][11][12]. In vivo, psychological and physical stress as well as the activation of the immune system alter cortisol release and can lead to an up to 10-fold increase in frequency and amplitude of secretion peaks.…”

Increased cyclic AMP levels enhance IL-1 alpha and IL-1 beta mRNA expression and protein production in human myelomonocytic cell lines and monocytes.

“…IL-1 secretion does not seem to occur via the conventional endoplasmic reticulum-Golgi route and the pathway for IL-I secretion is still unidentified. Besides transcriptional regulation, IL-1 synthesis is regulated posttranscriptionally (7-9), either at the translational level, like tumor necrosis factor (TNF)I (10), or at the secretory level (8).…”