Glucocorticoid receptor isoforms in steroid dependent asthma

INTRODUCTION: Ineffective response to glucocorticoids (GCs) in severe asthma may result from enhanced T cell activation, immune dysregulation, or altered expression of glucocorticoid receptor (GR). OBJECTIVES: The aim of the study was to analyze the expression of GR isoforms and in vitro sensitivity of lymphocytes to GCs in severe, steroid dependent asthma. PATIENTS AND METHODS: We analyzed the immunophenotype of peripheral blood lymphocytes, the effect of dexamethasone (DEX) on lymphocyte activation and proliferation, and the levels of GRα and GRβ mRNA in peripheral blood lymphocytes of 11 healthy subjects, 15 moderate asthmatics, 11 severe asthmatics on low dose oral GCs, and 14 severe asthmatics with suboptimal symptom control on high dose oral GCs. RESULTS: The average level of GRβ mRNA in lymphocytes was more than 300 fold lower than GRα, and this ratio was comparable in all groups. Lymphocytes from steroid dependent asthmatics were sensitive to steroids in in vitro activation assays, as evidenced by a significant decrease in activation antigen (CD25, CD69) expression, and inhibition of mitogen induced proliferation upon incubation with DEX. The results of in vitro functional assays were similar in all groups and did not correlate with the GRα/GRβ ratio. CONCLUSIONS: Steroid dependency in severe asthma is not associated with GRβ upregulation in lymphocytes or abnormal T cell reactivity in the presence of GCs. These data suggest that testing for the expression of GRα and GRβ isoforms in blood lymphocytes will not be useful in predicting sensitivity to GCs in severe asthma.