Relevance of multidrug resistance 1 and P-glycoprotein to drug resistance in patients with systemic lupus erythematosus

Abstract

Although corticosteroids and immunosuppressants are widely used for the treatments of various autoimmune diseases such as systemic lupus erythematosus (SLE), we often experience patients with SLE who are resistant to these treatments. Pglycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, is known to play a pivotal role in the acquisition of drug resistance to chemotherapies in malignancy. However, the relevance of MDR-1 and P-gp to resting and activated lymphocyte, major targets of the treatments in autoimmune diseases, remains unclear. We found that peripheral lymphocytes in patients with SLE express Pgp on the surface and its expression is highly correlated with disease activity. P-gp on lymphocytes is induced by not only genotoxic stresses but also activation stimuli such as cytokines, resulting in active efflux of corticosteroids from cytoplasm of lymphocytes, resulting in drug-resistance and high disease activity. However, the addition of P-gp antagonists such as ciclosporin A and inhibitors of P-gp synthesis successfully reduce efflux of corticosteroids from lymphocytes in vitro and these results imply that P-gp antagonists and P-gp synthesis inhibitors could work in order to overcome drug-resistance in vivo. Therefore, we propose that the measurement of P-gp on lymphocytes is a useful marker to indicate drug resistance and requirement of antagonists and/or intensive treatments to overcome drug resistance in active SLE patients