Expression profiling of ABC transporters in peripheral blood lymphocytes and monocyte-derived macrophages of rheumatoid arthritis patients

R. Oerlemans, M Blits, BAC Dijkmans, JW van der Heijden, WF Lems, GL Scheffer, Rieneke van de Ven, GJ Peters, Yehuda G. Assaraf, RJ Scheper, G Jansen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

In autoimmune diseases like rheumatoid arthritis (RA), multidrug resistance (MDR) transporters of the ATP-binding cassette (ABC) transporter superfamily harbor dual functions by extruding pro-inflammatory mediators and exporting disease modifying anti-rheumatics drugs (DMARDs), hence contributing to diminished treatment response. Herein we determined the expression (mRNA/protein) and functional efflux activities of multiple selected ABC transporters in immune-effector cells of RA patients in relation to DMARD response. ABC transporter profiling included ABCB1 (P-glycoprotein), ABCC1-6/ABCC10-12 (multidrug resistance proteins 1-9) and ABCG2 (Breast Cancer Resistance Protein). Analyses were performed in peripheral blood lymphocytes (PBL) and monocyte-derived macrophages (MDM) obtained from 52 RA patients (DMARD-naïve and DMARD (non)-responders) and HC (n = 19) using PCR, immunohistochemistry and flow cytometry. Notwithstanding the large inter-patient variabilities, PBLs from RA patients displayed significantly higher mRNA levels of ABCC1 (2.1-fold), ABCC4 (1.6-fold) and ABCC10 (1.9-fold) compared with HC. Expression levels of ABCB1, ABCC1, ABCC4 and ABCC10 were significantly and positively correlated with each other. Furthermore, significantly increased ABCG2 mRNA (2.8-fold) and protein levels (2.4-fold) were observed in MDM from RA patients compared to HC. Additional analyses revealed that a 1.8-fold increased functional activity of ABCB1 in CD3+ cells in RA patients receiving DMARD treatment versus DMARD-naïve patients, was exclusively contributed by DMARD non-responders. Although up to 1.7-fold higher levels of MDR mRNA levels were noted in PBL of DMARD non-responders over DMARD responders, these differences were not statistically significant. Together, these results underscore the involvement of multiple ABC transporters in immune-competent cells in relation to RA and DMARD response.
Original languageEnglish
Article number2020.02.007
Pages (from-to)47-60
Number of pages14
JournalJournal of Molecular and Clinical Medicine
Volume3
Issue number2
DOIs
Publication statusPublished - 20 Jun 2020

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