Introduction: Despite advances in lupus nephritis (LN) management, many patients fail to respond to first-line therapy or relapse after remission.Overexpression of P-glycoprotein (p-gp) on Plasma cells (PCs) and T-helper 17 lymphocytes (Th17) cells may contribute to disease activity and a drug-resistant phenotype in lupus nephritis (LN).P-gp has been linked to corticosteroid resistance.Emerging evidence suggests IL-17 signaling through the TAK-1/C/EBP- axis may modulate P-gp expression.Objective: Evaluation of role of downstream IL-17 mediated pathway (IL-17/TAK-1/C/EBP- pathway) in upregulation of P-gp expression in PCs and lymphocytes of LN and their contribution in the refractoriness to immunosuppressive treatment.Methods: We analyzed peripheral blood PCs and Th17 cells for P-gp expression in LN patients.U266B1 plasma cells were treated with IL-17, IL-6, and their inhibitors-anti-IL-6 + anti-IL-17, IL-17 + (5Z)-7oxozeaenol (TAK-1 inhibitor), and IL-17 + ST101 (C/EBP- inhibitor)for 24 hours.Plasma levels of NGAL, IL-17, IL-6, TNF-, CXCL12, and CXCL13 were quantified by ELISA.Results: 49 LN patients (refractory n=11; active n=20; inactive n=18) and 15 healthy controls were studied.Frequencies of CD38 + CD138 + PCs, and P-gp + PCs, Th17, P-gp + Th17, were significantly elevated in refractory and active LN compared with inactive LN and controls, which decreased after 3 months of standard therapy.IL-17, IL-6, TNF-
Singh et al. (Wed,) studied this question.