Expression of Corticosteroid Regulated Genes By Peripheral Blood Mononuclear Cells in Children with Asthma

Publication date: Available online 27 July 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Elena Goleva, Denise C. Babineau, Michelle A. Gill, Leisa P. Jackson, Baomei Shao, Zheng Hu, Andrew H. Liu, Cynthia M. Visness, Christine A. Sorkness, Donald Y.M. Leung, Alkis Togias, William W. Busse

Abstract

Background

Variability in response to inhaled corticosteroids may result in less than optimal asthma control and development of biomarkers assessing therapeutic efficacy of corticosteroids is important.

Objective

To examine whether in vitro peripheral blood mononuclear cell (PBMC) responses to corticosteroids relate to the clinical inhaled corticosteroid response.

Methods

PBMC were collected from 125 children with asthma (6-17 years) at enrollment (Visit 0, V0) and after one year of bimonthly guidelines-based management visits (Visit 6, V6). Difficult- versus easy-to-control asthma were defined as requiring daily therapy with ≥500 μg of fluticasone propionate (FLU) with/without a long-acting beta-agonist versus requiring ≤100 μg of FLU in at least 4 visits. mRNA levels of glucocorticoid receptor alpha (GRalpha), corticosteroid transactivation (FK binding protein 5 (FKBP5)) and transrepression markers (IL-8, TNFalpha) were measured by RT-PCR in freshly isolated cells and in response to 10^-8 M FLU.

Results

Compared to easy-to-control, PBMC of difficult-to-control asthma had significantly lower GRalpha at V0 (p=0.05). A 30% increase in IL-8 suppression by FLU (p=0.04) and a trend for increased TNFalpha suppression by FLU between V0 and V6 (p=0.07) were observed in easy-to-control asthma. In contrast, no changes between V0 and V6 in the IL-8 and TNFalpha suppression by FLU were observed in difficult-to-control asthma. Corticosteroid-mediated transactivation (FKBP5 induction by FLU) increased in the PBMC of difficult- and easy-to-control asthma between V0 and V6 (p=0.05 and p=0.03 respectively).

Conclusions

PBMC of children with difficult-to-control asthma treated with guidelines-based therapy and requiring high dose inhaled corticosteroids had reduced in vitro responsiveness to corticosteroids.

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