P-glycoprotein expression in circulating blood leukocytes of patients with steroid-resistant asthma.
P-Glycoprotein is a transmembrane efflux pump for different lipophilic drugs including glucocorticosteroids. Thus, upregulation of P-glycoprotein may provide a mechanism for reduced glucocorticosteroid responses as they occur in steroid-resistant asthma. To address this issue, we have examined freshly isolated peripheral blood mononuclear cells and granulocytes with regards to P-glycoprotein functional and surface expression. Using two-color immuno fluorescence techniques, we demonstrated a direct correlation between the efflux of the fluorescent dye Rh 123 and P-glycoprotein surface expression in lymphocytes, NK (natural killer) cells, monocytes and granulocytes. P-Glycoprotein levels varied widely between different leucocytes, with NK cells and CD8+ T cells having high, and granulocytes having no detectable levels. There was no evidence for upregulation of P-glycoprotein expression in any cell type from patients with steroid-resistant asthma compared to patients with steroid-sensitive or mild asthma. These results suggest that increased P-glycoprotein expression can be excluded as a mechanism for steroid resistance. Interestingly, a down regulation of P-glycoprotein expression in B cells was associated with systemic glucocorticosteroid treatment in vivo and in vitro. Whether this phenomenon may account for reduced immunoglobulin levels associated with oral glucocortico-steroid therapy remains to be determined.
Montano
E
E
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
Schmitz
M
M
Blaser
K
K
Simon
H U
HU
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism* / Q000502:physiology*; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance; D004804:Eosinophils / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use*; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D007963:Leukocytes, Mononuclear; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015703:Antigens, CD; D005938:Glucocorticoids; D003907:Dexamethasone