Low dose interleukin-2 decreases P-glycoprotein activity and exerts synergistic anti-inflammatory effects with immunosuppressants in the treatment of lupus nephritis with steroid and immunosuppressive drug resistance

Abstract

Objective P-glycoprotein (P-gp) is capable of transporting glucocorticoids and immunosuppressants out of lymphocytes, resulting in drug resistance in lupus nephritis (LN). IL-2 decreases P-gp expression in cultured cells from human colon carcinoma. Here, we investigated the effects of low-dose IL-2 on the functionality of P-gp in PBMCs of steroid resistant LN patients and in kidneys in MRL/lpr mice. Methods 30 drug resistant LN patients were treated with glucocorticoids and immunosuppressants with or without low-dose IL-2 for 12 weeks. Serum and urine collected before and after treatment were analyzed for anti-dsDNA, C3, C4, renal and liver function. P-gp expression and activity were detected in PBMCs by flow cytometry and rhodamine 123. MRL/lpr mice were treated with methylprednisolone (MP) with or without IL-2 for 4 weeks. Pathological changes as well as protein and mRNA expression of P-gp were assessed in kidneys. Results Compared to patients without IL-2 treatment, the patients treated with IL-2 had higher serum C3 (p=0.01) and C4 levels (p=0.04), while lower proteinuria(p=0.04), serum creatinine (p=0.03), anti-dsDNA levels (p< 0.001), and accordingly lower SLEDAI (p=0.03). These modifications were associated with reduced P-gp expression (p< 0.01) and activity (p=0.02) in PBMCs. Moreover, compared with controls, MRL/lpr mice treated with IL-2 and MP showed reduced proteinuria (p=0.002) and fewer acute and chronic renal pathological lesions. IL-2 attenuated renal deposition of IgG/C3, decreased renal expression of P-gp. Conclusion Low-dose IL-2 decreases P-gp activity and exerts synergistic anti-inflammatory effects with immunosuppressants in the treatment of LN with steroid and immunosuppressants resistance.