Dose-Related Inhibition of Proinflammatory Cytokine Release from Neutrophils of the Newborn by Dexamethasone, Betamethasone, and Hydrocortisone

Abstract

The objective of this study was to determine the doses of dexamethasone (DEX), betamethasone (BET), and hydrocortisone (HC) that effectively inhibit the release of two potent proinflammatory chemokines, interleukin 8 (IL-8) and macrophage inflammatory protein alpha (MIP), from polymorphonuclear neutrophils (PMNs) of the newborn. Human PMNs were isolated from cord blood (n = 18). Chemokines were measured from PMN cell culture supernatants after 18 h of stimulation using tumor necrosis factor (1 ng/ml), with and without pretreatment by DEX (10^–10 to 10^–6 M) versus HC or BET (10^–10 to 10^–5 M). Maximal inhibitions of IL-8 release by BET, DEX, and HC were 97, 91, and 91%, respectively. For MIP, the maximal inhibitions by BET, DEX, and HC were 88, 69, and 70%, respectively. The 50% inhibitory concentrations by DEX, BET, and HC for IL-8 release were 3.4 ± (SE) 1.6 × 10^–9, 1.8 ± 7.4 × 10^–8, and 1.8 ± 0.5 × 10^–7 M, respectively. The 50% inhibitory concentrations by DEX, BET, and HC for MIP release were 1.0 ± (SE) 0.5 × 10^–8, 3.8 ± 3.1 × 10^–8, and 4.8 ± 1.6 × 10^–7 M, respectively. In vitro, these corticosteroids effectively inhibited the release of two structurally different chemokines that are found in the airway lavage fluids of infants developing bronchopulmonary dysplasia. When compared to plasma DEX levels previously reported during the treatment of bronchopulmonary dysplasia, our results suggest that the doses of DEX, and potentially BET, needed to treat chronic lung disease may be more than five to ten times lower than those of current DEX regimens.