GRβ expression in nasal polyp inflammatory cells and its relationship to the anti-inflammatory effects of intranasal fluticasone

Abstract

Background: Nasal polyposis disease is an inflammatory disorder with intense eosinophilic infiltration of respiratory mucosa that is often difficult to control with topical steroids. Recent evidence suggests that overexpression of the glucocorticoid receptor splice variant GRβ in inflammatory cells might contribute to steroid insensitivity in diseases such as asthma. Objective: The purposes of this investigation were to determine whether nasal polyp (NP) inflammatory cells overexpress GRβ and to examine whether GRβ overexpression is associated with insensitivity to the potent topical steroid fluticasone propionate (FP). Methods: Biopsies were obtained from 10 subjects with NPs before and 4 weeks after treatment with intranasal FP. Middle turbinates biopsies from 6 healthy, nonallergic subjects served as normal controls. Biopsies were immunostained for inflammatory cell markers as well as GRβ and probed for various cytokine mRNA. The anti-inflammatory response to FP was examined in relation to pretreatment levels of GRβ expression. Results: The total numbers of inflammatory cells were increased in NPs. The percentage of inflammatory cells expressing GRβ was also increased (40.5% ± 19.2% vs 16.1% ± 4.0%, P = .009). GRβ expression in NPs was almost exclusive to T lymphocytes, eosinophils, and macrophages. An inverse correlation was observed between the baseline inflammatory cell GRβ expression and the reduction after FP treatment in EG2-positive eosinophils, CD4-positive T lymphocytes, endothelial VCAM-1 expression, and IL-4 mRNA-positive cells. NPs that were “FP-insensitive” in terms of suppression of eosinophil numbers (major basic protein–positive) had a significantly greater percentage of GRβ-positive inflammatory cells, a higher ratio of GRβ-positive/GRα-positive cells, and increased numbers of GRβ-positive eosinophils and macrophages in comparison with those that were “FP-sensitive.” “FP-insensitive” NPs also demonstrated a higher percentage of IL-5–positive inflammatory cells expressing GRβ before and after FP treatment. Conclusion: GRβ expression appears to be a marker of steroid insensitivity in NPs. Expression of GRβ by NP inflammatory cells, particularly T cells and eosinophils, might render them resistant to suppression by topical steroids and thereby contribute to persistent NP inflammation. (J Allergy Clin Immunol 2001;108:59-68.)