Is steroid resistance related to multidrug resistance-I (MDR-I) in rheumatoid arthritis?
Both healthy ageing and rheumatoid arthritis (RA) are frequently associated with acquired steroid resistance. Here, we investigated the potential involvement of steroid resistance with multidrug resistance (MDR) and explored the impact of pathological ageing on lymphocyte sensitivity to glucocorticoids. Seventy-four RA patients and 26 healthy controls took part in this study. Peripheral blood mononuclear cells were isolated and T-cell sensitivity to glucocorticoids was measured in vitro. The functional activity of P-glycoprotein was analyzed by flow cytometry and ABCB1/MDR-1 gene polymorphisms were assessed in peripheral lymphocytes. Patients and controls had similar sensitivities to glucocorticoids. Only controls presented age-related immunological changes, including reduced T-cell proliferation and relative resistance to corticosterone. Patients had a higher percentage (72%) of lymphocytes actively extruding rhodamine 123 (Rh123(dim)) than controls (60%) in spite of similar P-glycoprotein activity. A higher percentage of Rh123(dim)+ lymphocytes was observed in patients who were more resistant to dexamethasone in vitro. The distribution of ABCB1 genotypes in RA patients did not differ significantly from that in controls and were not associated to steroid sensitiveness or disease activity. These data suggest that peripheral lymphocytes of arthritic patients are fully responsive to GCs in vitro in spite of displaying higher MDR activity.
Borowski
Luciana C
LC
Laboratory of Cellular and Molecular Immunology, Instituto de Pesquisas Biomédicas, Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Lopes
Rodrigo P
RP
Gonzalez
Tatiana P
TP
Dummer
Luana A
LA
Chies
José Artur B
JA
Silveira
Inês G
IG
Keisermann
Mauro
M
Bauer
Moisés E
ME
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000367:Age Factors; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D005787:Gene Frequency; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011110:Polymorphism, Genetic; D020112:Rhodamine 123 / Q000378:metabolism
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018501:Antirheumatic Agents; D005938:Glucocorticoids; D027361:Organic Anion Transporters; D010835:Phytohemagglutinins; D020112:Rhodamine 123; D003907:Dexamethasone