Regulation of P-glycoprotein through CaMKII/cPLA2 pathway in lymphocytes for treating refractory rheumatoid arthritis by manidipine

Background: Overexpression of P-glycoprotein (P-gp) in the lymphocytes were observed with patients with refractory rheumatoid arthritis (RRA) in previous clinical studies, which correlated with the resistance to multiple disease-modifying antirheumatic drugs (DMARDs). The underlying mechanisms is unknown, which leading to unmet therapeutic approach for RRA.

Methods: A modified adjuvant-induced arthritis (AA) rat model with overexpression of P-gp in lymphocytes and resistance to methotrexate (MTX) treatment at the reported anti-arthritis dosage was previous build and used for examining the anti-arthritic effects of MA in combination with MTX. Moreover, knock-down of CaMKII were used on P-gp overexpression THP-1 cell lines to understanding the underlying mechanisms of MA.

Results: MTX alone did not show anti-arthritis effects on AA model, while treatment of MA overcome the resistance to MTX by reducing the enhanced P-gp expression and enhancing the anti-arthritic effects of MTX in the AA rat model. Moreover, MA overcame the MTX resistance and improved the anti-inflammatory effect of MTX in P-gp-THP-1 cells as well as the lymphocytes isolated from AA rats. Mechanistically, our data indicated that MA reduced the P-gp expression through the CaMKII/cPLA2 pathway, leading to increased accumulation of rhodamine 123 and FITC-MTX.

Conclusion: The elevated levels of CaMKII and cPLA2 contribute to the increased levels of P-gp (ABCB1) in lymphocytes of RRA with an inadequate response to MTX, revealing a novel mechanism of resistance. For the first time, our study indicated that MA maybe a promising treatment to overcome the MTX resistance in patients with active RRA.

CaMKII/cPLA2 pathway; Lymphocytes; Manidipine; P-glycoprotein; Refractory rheumatoid arthritis.