通过CaMKII/cPLA2途径调节淋巴细胞p -糖蛋白治疗难治性类风湿关节炎

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-04-26 DOI:10.1016/j.intimp.2025.114735

Yan-Hua YAN , Qi-Lu LI , Biao QU , Qiu-Chan HUAN , Xuan-Tong QIU , Yue QU , Hua ZHOU , Ying XIE

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引用次数: 0

摘要

背景既往临床研究发现难治性类风湿关节炎（RRA）患者淋巴细胞中p -糖蛋白（P-gp）的高表达与多种抗风湿药物（DMARDs）的耐药相关。其潜在机制尚不清楚，这导致RRA的治疗方法尚未得到满足。方法建立a修饰佐剂诱导关节炎（AA）大鼠模型，模型中P-gp在淋巴细胞中过表达，对甲氨蝶呤（MTX）抗关节炎剂量产生耐药性，用于观察a修饰佐剂联合MTX的抗关节炎作用。此外，在P-gp过表达的THP-1细胞系上敲除CaMKII以了解MA的潜在机制。结果单用smtx对AA大鼠模型无抗关节炎作用，而MA通过降低P-gp表达，增强MTX抗关节炎作用，克服MTX对AA大鼠模型的耐药作用。此外，MA克服了MTX耐药性，提高了MTX对AA大鼠P-gp-THP-1细胞和淋巴细胞的抗炎作用。在机制上，我们的数据表明，MA通过CaMKII/cPLA2途径降低P-gp的表达，导致罗丹明123和FITC-MTX的积累增加。结论CaMKII和cPLA2水平升高导致MTX反应不足的RRA淋巴细胞P-gp （ABCB1）水平升高，揭示了一种新的耐药机制。我们的研究首次表明，MA可能是一种很有希望的治疗方法，可以克服活动性RRA患者的MTX耐药。

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

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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.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.