Dexamethasone Antagonizes IL-4 and IL-10-Induced Release of IL-IRA by Monocytes but Augments IL-4-, IL-10-, and TGF-β-Induced Suppression of TNF-α Release

Abstract

The activities of monocyte-derived tumor necrosis factor (TNF)-α and interleukin (IL)-1β are potentially modified by IL-1RA and soluble receptors for TNF (sTNF-R), which are themselves monocyte products. IL-4, IL-10, TGF-β, and glucocorticoids (GC) all suppress the lipopolysaccharide (LPS)-stimulated release of TNF-α and IL-1β but vary in their effects on IL-1RA and sTNF-R. This raises the prospect of interactions between the cytokines and glucocorticoids, which may be antagonistic or additive on IL-1 and TNF activity. We, therefore, studied the interactions of the GC dexamethasone (Dex) with IL-4, IL-10, and transforming growth factor (TGF)-β on the release of TNF-α and IL-1RA by human monocytes and the monocytic THP-1 cell line. Low concentration of Dex (10^-8-10^-7 M) acted additively with low concentrations of IL-4 (0.01-1 ng/ml), IL10 (0.01-0.1 U/ml), or TGF-β (0.01-1 ng/ml) to profoundly suppress LPS-stimulated release of TNF-α by whole blood and, to a lesser degree, THP-1 cells. Dex also suppressed spontaneous release of IL-1RA from PBMC and THP-1 cells, whereas IL-4 and IL-10, but not TGF-β, stimulated release. Dex antagonized the enhanced release in IL-4 and IL-10-stimulated cultures. The capacity to stimulate release of IL-1RA may contribute to the anti-inflammatory potential of IL-4 and IL-10 in monocyte/macrophage-mediated disease. GC, therefore, do not uniquely enhance the suppressive functions of IL-4 and IL-10 on monokine activity. The therapeutic benefit of combinations of GC and IL-4, Iβ10 or TGF-β in disease may depend on the roles of the individual monokines and antagonists in pathogenesis.