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

Background: Nasal polyposis disease is an inflammatory disorder with intens e eosinophilic infiltration of respiratory mucosa that is often difficult t o control with topical steroids. Recent evidence suggests that overexpressi on of the glucocorticoid receptor splice variant GR beta in inflammatory ce lls might contribute to steroid insensitivity in diseases such as asthma. Objective: The purposes of this investigation were to determine whether nas al polyp (NP) inflammatory cells overexpress GR beta and to examine whether GR beta overexpression is associated with insensitivity to the potent topi cal steroid fluticasone propionate (FP). Methods: Biopsies were obtained from 10 subjects with NPs before and 4 week s after treatment with intranasal FP. Middle turbinates biopsies from 6 hea lthy, nonallergic subjects served as normal controls. Biopsies were immunos tained for inflammatory cell markers as well as GR beta and probed for vari ous cytokine mRNA. The anti-inflammatory response to FP was examined in rel ation to pretreatment levels of GR beta expression. Results: The total numbers of inflammatory cells were increased in NPs. The percentage of inflammatory cells expressing GR beta was also increased (40 .5% +/- 19.2% vs 16.1% +/- 4.0%, P = .009). GR beta expression in NPs was a lmost exclusive to T lymphocytes, eosinophils, and macrophages. An inverse correlation was observed between the baseline inflammatory cell GR beta exp ression and the reduction after FP treatment in EG2-positive eosinophils, C D4-positive T lymphocytes, endothelial VCAM-1 expression, and IL-4 mRNA-pos itive cells. NPs that were "FP-insensitive" in terms of suppression of eosi nophil numbers (major basic protein-positive) had a significantly greater p ercentage of GR beta -positive inflammatory cells, a higher ratio of GR bet a -positive/GR alpha -positive cells, and increased numbers of GR beta -pos itive eosinophils and macrophages in comparison with those that were "FP-se nsitive" "FP-insensitive" NPs also demonstrated a higher percentage of IL-5 -positive inflammatory cells expressing GR beta before and after FP treatme nt. Conclusion: GR beta expression appears to be a marker of steroid insensitiv ity in NPs. Expression of GR beta by NP inflammatory cells, particularly T cells and eosinophils, might render them resistant to suppression by topica l steroids and thereby contribute to persistent NP inflammation.