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Expression of corticosteroid-regulated genes by PBMCs in children with asthma
Elena Goleva1, Denise C Babineau2, Michelle A Gill3
1Department of Pediatrics, National Jewish Health, Denver, Colo.
Insights
Children with difficult-to-control asthma show reduced in vitro corticosteroid responsiveness in PBMCs. This finding highlights potential biomarkers for assessing inhaled corticosteroid (ICS) efficacy in asthma management.
Area of Science:
- Immunology
- Pharmacology
- Pediatric Pulmonology
Background:
- Variability in inhaled corticosteroid (ICS) response impacts asthma control.
- Developing biomarkers for corticosteroid efficacy is crucial for personalized asthma treatment.
Purpose of the Study:
- To investigate the relationship between in vitro peripheral blood mononuclear cell (PBMC) responses to corticosteroids and clinical ICS response in children with asthma.
- To identify potential biomarkers for predicting ICS treatment outcomes.
Main Methods:
- PBMCs were collected from 125 children with asthma (aged 6-17 years) at baseline and after one year of guideline-based management.
- Asthma control was categorized as difficult-to-control or easy-to-control based on ICS dosage.
- mRNA levels of glucocorticoid receptor α, FK506-binding protein 5, IL-8, and TNF-α were measured by RT-PCR, assessing both baseline and corticosteroid-induced responses.
Main Results:
- PBMCs from children with difficult-to-control asthma exhibited lower glucocorticoid receptor α levels at baseline compared to those with easy-to-control asthma.
- Children with easy-to-control asthma showed increased IL-8 and TNF-α suppression by fluticasone propionate (FLU) over one year, while those with difficult-to-control asthma did not.
- Corticosteroid-mediated transactivation (FK506-binding protein 5 induction) increased in PBMCs of both easy-to-control and difficult-to-control asthma groups.
Conclusions:
- Children with difficult-to-control asthma requiring high-dose ICSs demonstrate reduced in vitro responsiveness to corticosteroids.
- These findings suggest that in vitro PBMC responses may serve as biomarkers for ICS therapeutic efficacy in pediatric asthma.
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 μg or more of fluticasone propionate (FLU) with or without a long-acting β-agonist versus 100 μg or less of FLU in at least 4 visits. mRNA levels of glucocorticoid receptor α and corticosteroid transactivation (FK506-binding protein 5) and transrepression markers (IL-8 and TNF-α) 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-to-control asthma, PBMCs from those with difficult-to-control asthma had significantly lower glucocorticoid receptor α levels at V0 (P = .05). A 30% increase in IL-8 suppression by FLU (P = .04) and a trend for increased TNF-α 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-α suppression by FLU were observed in patients with difficult-to-control asthma. Corticosteroid-mediated transactivation (FK506-binding protein 5 induction by FLU) increased in the PBMCs of patients with difficult-to-control 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.
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