Expression of corticosteroid-regulated genes by PBMCs in children with asthma

Abstract

Background: Variability in response to inhaled corticosteroids (ICSs) can result in less than optimal asthma control. Development of biomarkers assessing the therapeutic efficacy of corticosteroids is important.Objective: We sought to examine whether in vitro PBMC responses to corticosteroids relate to the clinical ICS response.Methods: PBMCs were collected from 125 children with asthma (6-17 years) at enrollment (visit 0 [V0]) and after 1 year of bimonthly guidelines-based management visits (visit 6 [V6]). Difficult-to-control and easy-to-control asthma were defined as requiring daily therapy with 500 mu g or more of fluticasone propionate (FLU) with or without a long-acting beta-agonist versus 100 mu g or less of FLU in at least 4 visits. mRNA levels of glucocorticoid receptor alpha and corticosteroid transactivation (FK506-binding protein 5) and transrepression markers (IL-8 and TNF-alpha) were measured by using RT-PCR in freshly isolated cells and in response to 10(-8) mol/L FLU.Results: Compared with PBMCs from patients with easy-tocontrol asthma, PBMCs from those with difficult-to-control asthma had significantly lower glucocorticoid receptor a levels at V0 (P = .05). A 30% increase in IL-8 suppression by FLU (P = .04) and a trend for increased TNF-alpha suppression by FLU between V0 and V6 (P = .07) were observed in patients with easy-to-control asthma. In contrast, no changes between V0 and V6 in IL-8 and TNF-alpha suppression by FLU were observed in patients with difficult-to-control asthma. Corticosteroidmediated transactivation (FK506-binding protein 5 induction by FLU) increased in the PBMCs of patients with difficult-tocontrol and easy-to-control asthma between V0 and V6 (P = .05 and P = .03, respectively).Conclusions: PBMCs of children with difficult-to-control asthma treated with guidelines-based therapy and requiring high-dose ICSs had reduced in vitro responsiveness to corticosteroids.