IMR Press / JMCM / Volume 3 / Issue 2 / DOI: 10.31083/j.jmcm.2020.02.007
Open Access Original Research
Expression profiling of ABC transporters in peripheral blood lymphocytes and monocyte-derived macrophages of rheumatoid arthritis patients
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1 Amsterdam Rheumatology and immunology Center, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands
2 Department of Pathology, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands
3 Department of Nephrology, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands
4 Department of Medical Oncology, Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands
5 Department of Otolaryngology, Amsterdam University Medical Center, location VUmc Center, Amsterdam, The Netherlands
6 Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
7 The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, The Technion Israel Institute of Technology, Haifa, Israel
J. Mol. Clin. Med. 2020, 3(2), 47–60; https://doi.org/10.31083/j.jmcm.2020.02.007
Submitted: 15 May 2020 | Accepted: 15 June 2020 | Published: 20 June 2020
Copyright: © 2020 Oerlemans et al. Published by IMR press.
This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).
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.

Keywords
ABC transporters
Multidrug resistance
DMARDs
drug efflux
rheumatoid arthritis
Figures
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