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

  • Int Immunopharmacol. 2025 May 27:156:114735. doi: 10.1016/j.intimp.2025.114735.
Yan-Hua Yan  1 ,  Qi-Lu Li  1 ,  Biao Qu  2 ,  Qiu-Chan Huan  1 ,  Xuan-Tong Qiu  1 ,  Yue Qu  1 ,  Hua Zhou  3 ,  Ying Xie  4
Affiliations
  • 1. Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangzhou University of Chinese Medicine, Guangdong, China; State Key Laboratory of Dampness syndrome of Chinese Medicine, The Second Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
  • 2. Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China.
  • 3. Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangzhou University of Chinese Medicine, Guangdong, China; State Key Laboratory of Dampness syndrome of Chinese Medicine, The Second Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China. Electronic address: [email protected].
  • 4. Chinese Medicine Guangdong Laboratory (Hengqin Laboratory), Guangzhou University of Chinese Medicine, Guangdong, China; State Key Laboratory of Dampness syndrome of Chinese Medicine, The Second Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China. Electronic address: [email protected].
PMID: 40294472 DOI: 10.1016/j.intimp.2025.114735
Abstract

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.

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