AB0060 METHOTREXATE DOWNREGULATES P-GLYCOPROTEIN EXPRESSION AND INHIBITS THE ACTIVATION OF JAK2/STAT3 PATHWAY IN RHEUMATOID ARTHRITIS PERIPHERAL BLOOD MONONUCLEAR CELLS
Authors: Kailin Chen, Qin Kaili, LI Xiaofeng, Caihong Wang
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by abnormal synovial hyperplasia, inflammatory cell infiltration, and destruction of cartilage or bone. Early use of disease-modifying anti-rheumatic drugs (DMARDs) can significantly improve the patient's condition. However, many patients had no response after treatment or gradually decreased after treatment for some time. DMARDs Multidrug resistance(MDR) is an important cause of the above phenomenon<sup>1</sup>. How to reverse MDR in RA patients, and then control the disease is a major problem in RA treatment. The mechanism of MDR is complex. ATP binding cassette transporter super family consists of 48 transporters, ABCB1/P-glycoprotein (P-gp) is one of the major proteins associated with MDR<sup>2</sup>. The expression of P-gp is induced not only by genotoxic mechanisms, but also by inflammatory cytokines such as IL-2, IL-4, IL-6, and TNF-α in some inflammatory diseases<sup>3,4</sup>. <h3>Objectives:</h3> The multiple drug resistance(MDR) to disease modifying anti-rheumatic drugs(DMARDs) is the key factor in Rheumatoid arthritis(RA) treatment field. P-glycoprotein (P-gp) encoded by multidrug resistance gene 1 (MDR1) is involved in the excretion of numerous DMARDs. We investigated the effects of methotrexate(MTX) alone and combined with interleukin 6 (IL-6) on P-gp expression and examined the signaling pathway involved in Peripheral blood mononuclear cells of RA patients. <h3>Methods:</h3> The Peripheral blood mononuclear cells were extracted from Fifteen RA patients who were without any DMARDs and biological agents treatment. These cells were treated with IL-6, IL-6+MTX(0.01ug/m), IL-6+MTX (0.1ug/m), IL-6+MTX (1ug/m) for 72h. P-gp expression was measured by flow cytometry and real-time polymerase chain reaction (RT-PCR); JAK2 and STAT3 were measured by RT-PCR. <h3>Results:</h3> Methotrexate produce a dose-responsive reduction of both P-gp, JAK2 and STAT3 expression induced by IL-6. <h3>Conclusion:</h3> Methotrexate downregulates p-glycoprotein expression and inhibits the activation of JAK2/STAT3 pathway in rheumatoid arthritis peripheral blood mononuclear cells. <h3>References</h3> [1] van der Heijden JW, Dijkmans BA, Scheper RJ, Jansen G. Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs-from bench to bedside. Nat Clin Pract Rheumatol. 2007 2007-01-01;3(1):26-34. [2] Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res, 2001,11:1156-1166. [3] Tsujimura S, Saito K, Nakayamada S, Nakano K, Tanaka Y. Clinical relevance of the expression of P-glycoprotein on peripheral blood lymphocytes to steroid resistance in patients with systemic lupus erythematosus. Arthritis Rheum. 2005 2005-06-01;52(6):1676-1683. <h3>Acknowledgement:</h3> National Natural Science Foundation of China(No. 81471618). <h3>Disclosure of Interests:</h3> None declared