title: Differential effect of exogenous interleukin-10 versus glucocorticoids on gene expression and pro-inflammatory cytokine release by polymorphonuclear leukocytes and monocytes of the newly born.
abstract: Bronchopulmonary dysplasia (BPD) is one of the most common causes of mortality and morbidity in neonatal intensive care units. Persistent inflammation, with an abnormal influx of polymorphonuclear leukocytes (PMNs) followed by monocytes (MONOs), occurs early in the pathogenesis of BPD. Anti-inflammatory therapy with better efficacy and safety than dexamethasone (DEX) is needed. In the present study we determined cell-specific gene expression and cytokine release in response to glucocorticoids versus interleukin-10 (IL-10). Subsequently, we hypothesized that the insensitivity of MONOs to DEX was associated with a failure of the glucocorticoid receptor to translocate to the nucleus. PMNs and MONOs were isolated from umbilical cord blood at birth, and pretreated with PBS vehicle, IL-10 or glucocorticoids prior to endotoxin (LPS)-stimulation for 4 and 18h. Genome-wide gene expressions were determined by microarray and validated by RT-qPCR. Interleukin 8 release in cell culture supernatant was measured by ELISA. To examine the mechanism of monocyte insensitivity to glucocorticoids, nuclear translocation of the glucocorticoid receptor was determined by Western blots. MONOs had 6 times the number of genes changing expression with IL-10 compared to PMNs at 4h. DEX at the therapeutic level for neonates with BPD had no effect on gene expression in MONOs. The order of potency for inhibition of interleukin-8 release from MONOs was IL-10 >betamethasone >dexamethasone and hydrocortisone. Glucocorticoid potency in MONOs was directly related to glucocorticoid receptor translocation to nucleus. Gene expression profiling for IL-10 versus glucocorticoids indicates there may be major differences in therapeutic efficacy for BPD.
authors: Division of Neonatal-Perinatal Medicine, Stony Brook Long Island Children's Hospital, Stony Brook NY 11794, USA.
authors: Dennis
authors: D
authors: Davidson
authors: Hardik
authors: H
authors: Patel
authors: Ana C
authors: AC
authors: Degoy
authors: Irina
authors: I
authors: Gershkovich
authors: Ivana
authors: I
authors: Vancurova
authors: Veronika
authors: V
authors: Miskolci
keywords: Bronchopulmonary dysplasia; dexamethasone; gene expression microarray; monocytes; polymorphonuclear leukocytes
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