Selective resistance to different glucocorticoids in severe autoimmune disorders.
Resistance to glucocorticoids often occurs in patients with severe inflammatory disorders. Occasionally, this resistance could be overcome by switching to a different glucocorticoid, but the mechanisms of this selectivity are not clear. We studied this condition in three patients with severe inflammatory disorders, who responded satisfactorily to betamethasone, but could not be switched to equipotent doses of methylprednisolone or prednisone. While betamethasone displayed similar activity on lymphocyte proliferation in cells obtained from the three patients and controls, higher concentrations of methylprednisolone were needed to inhibit proliferation in patients' cells. In a competition study, the concentration of methylprednisolone that inhibited 50% of specific [(3)H]dexamethasone binding was increased in patients' lymphocytes. Higher Rhodamine-123 efflux was demonstrated in CD4 T cells from two patients, suggesting that an increased activity of membrane transporters could be responsible for the selective response to different glucocorticoids, even if P-glycoprotein and MRP1 expression was not increased.
Drigo
Ilenia
I
Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy.
Piscianz
Elisa
E
Valencic
Erica
E
De Iudicibus
Sara
S
Tommasini
Alberto
A
Ventura
Alessandro
A
Decorti
Giuliana
G
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D001623:Betamethasone / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002648:Child; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004351:Drug Resistance; D005260:Female; D005434:Flow Cytometry; D005562:Formazans / Q000737:chemistry; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007223:Infant; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008775:Methylprednisolone / Q000627:therapeutic use; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011239:Prednisolone / Q000627:therapeutic use; D013778:Tetrazolium Salts / Q000737:chemistry; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001623:Betamethasone; D004247:DNA; D005562:Formazans; D005938:Glucocorticoids; D008775:Methylprednisolone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011239:Prednisolone; D013778:Tetrazolium Salts; C079782:MTT formazan; C421109:multidrug resistance-associated protein 1