Mechanism for Dexamethasone Inhibition of Neutrophil Migration upon Exposure to Lipopolysaccharide in Vitro: Role of Neutrophil Interleukin-8 Release

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Abstract
The mechanism by which dexamethasone (DEX) inhibits neutrophil (PMN) recruitment to a site of inflammation, such as the newborn lung with bronchopulmonary dysplasia, is not completely understood. The aim of our study was to determine whether DEX inhibits neutrophil-induced neutrophil recruitment by inhibition of interleukin- (IL) 8 release from PMNs, and if there are developmental differences. PMNs isolated from cord blood (CB) and adults (A) were studied. We first measured the effect of DEX (10−10 to 10−4 M) on PMN migration to an exogenous IL-8 standard (10−8 M) using PMNs of CB (n= 3) and A (n= 3), over 1 h in a chemotaxis chamber. Second, we determined the effect of DEX (0 and 10−10 to 10−6 M) on IL-8 release (immunoasay) from PMNs of CB (n= 7) or A (n= 7) after incubation with lipopolysaccharide (LPS, 1 ng/mL) for 6 and 18 h. Third, the chemoattractant activity of culture media from the second experiment was studied with and without IL-8 antibody. DEX at concentrations of 10−10 to 10−4 M had no direct effect on PMN migration in vitro to an exogenous IL-8 standard. After LPS exposure, IL-8 release was greatly increased for PMNs from CB compared with A. DEX (10−10 to 10−4 M) resulted in a dose-dependent inhibition of IL-8 release from PMNs exposed to LPS for 6 and 18 h incubation. Increased PMN migration activity was only found with media of PMNs of CB with no DEX. At 18 h, media-induced migration activity was decreased if DEX (10−7 M), IL-8 antibody, or DEX (10−7 M) with IL-8 antibody were present during the incubation with LPS: there was an 88, 86, and 101% reduction in migration activity, respectively. We conclude that DEX inhibits PMN-induced PMN migration, predominantly via inhibition of IL-8 release for PMNs of the newborn. We suggest that a 10-fold lowering of the standard DEX dose may effectively reduce lung inflammation in bronchopulmonary dysplasia.

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