Investigating the interaction between aryl hydrocarbon receptor and methotrexate: implications for treatment resistance in rheumatoid arthritis patients.
Anna Wajda, Gabriela Filipowicz, Yana Kaliberda, Barbara Stypińska, Tomasz Kmiołek, Ewa Kuca-Warnawin, Małgorzata Jarończyk, Agata Matusiewicz, Bożena Jaszczyk, Małgorzata Stasiek, Anna Felis-Giemza, Katarzyna Bazała, Adam Ejma-Multański, Diana Bogucka, Ewa Modzelewska, Marzena Olesińska, Agnieszka Paradowska-Gorycka
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引用次数: 0
Abstract
Background: The aryl hydrocarbon receptor (AHR) plays a key role in immune regulation and drug metabolism, potentially influencing methotrexate (MTX) treatment outcomes in patients with rheumatoid arthritis (RA). This exploratory study investigated the relationship between AHR activity and MTX responsiveness, and examined whether combination therapy with tocilizumab (TCZ), an interleukin (IL)-6 receptor inhibitor, could influence MTX resistance and treatment response.
Methods: We employed in silico docking to assess MTX binding to the AHR Per-Arnt-Sim (PAS)-B domain. Ex vivo and in vitro models using peripheral blood mononuclear cells (PBMCs) from RA patients and healthy donors were also used. Flow cytometry was used to analyze AHR expression across immune cell subtypes. Additionally, HepG2 cells served as a pharmacological model to study the interaction of MTX and TCZ with AHR and the expression of drug transporter genes.
Results: AHR expression was significantly higher in monocytes from good responders to MTX than in those from poor responders and MTX-intolerant patients, suggesting that monocytes were the PBMC subset most strongly associated with AHR-related patterns of MTX response. In silico analysis supported the binding of MTX to the PAS-B domain of AHR. The in vitro model confirmed that monocytes were the most responsive subset in the context of AHR-related changes. Treatment with TCZ tended to reduce the proportion of AHR-positive monocytes, whereas co-treatment with MTX shifted AHR toward a pattern comparable to that in good responders or under control conditions.
Conclusions: Our findings underscore the complexity of MTX pharmacodynamics and highlight AHR as a potential biomarker for predicting treatment response in RA patients. The combination of MTX and TCZ modulated AHR activity and could inform personalized therapeutic strategies, especially in patients exhibiting MTX resistance or intolerance. While preliminary, this multi-layered investigation-combining patient samples, 3D cultures, and molecular docking-supports further research into AHR-modulating therapies in RA.
背景：芳烃受体（AHR）在免疫调节和药物代谢中起关键作用，可能影响类风湿关节炎（RA）患者甲氨蝶呤（MTX）治疗的结果。本探索性研究探讨了AHR活性与MTX反应性之间的关系，并探讨了与白细胞介素(IL)-6受体抑制剂tocilizumab （TCZ）联合治疗是否会影响MTX耐药性和治疗反应。方法：我们采用硅对接来评估MTX与AHR per - art - sim (PAS)-B结构域的结合。使用RA患者和健康供者外周血单个核细胞（PBMCs）的离体和体外模型也被使用。流式细胞术分析AHR在不同免疫细胞亚型中的表达。此外，以HepG2细胞为药理学模型，研究MTX和TCZ与AHR的相互作用以及药物转运基因的表达。结果：MTX良好应答者的单核细胞中AHR表达明显高于不良应答者和MTX不耐受患者的单核细胞，表明单核细胞是与AHR相关的MTX应答模式最密切相关的PBMC亚群。硅分析支持MTX与AHR的PAS-B结构域的结合。体外模型证实，单核细胞是ahr相关变化背景下反应最灵敏的亚群。用TCZ治疗倾向于降低AHR阳性单核细胞的比例，而与MTX联合治疗将AHR转向与良好反应者或对照条件下相似的模式。结论：我们的研究结果强调了MTX药效学的复杂性，并强调了AHR作为预测RA患者治疗反应的潜在生物标志物。MTX和TCZ联合使用可调节AHR活性，并可为个性化治疗策略提供信息，特别是在MTX耐药或不耐受的患者中。虽然是初步的，但这项多层调查——结合患者样本、3D培养和分子对接——支持进一步研究RA中ahr调节疗法。临床试验号：不适用。
期刊介绍：
Pharmacological Reports publishes articles concerning all aspects of pharmacology, dealing with the action of drugs at a cellular and molecular level, and papers on the relationship between molecular structure and biological activity as well as reports on compounds with well-defined chemical structures.
Pharmacological Reports is an open forum to disseminate recent developments in: pharmacology, behavioural brain research, evidence-based complementary biochemical pharmacology, medicinal chemistry and biochemistry, drug discovery, neuro-psychopharmacology and biological psychiatry, neuroscience and neuropharmacology, cellular and molecular neuroscience, molecular biology, cell biology, toxicology.
Studies of plant extracts are not suitable for Pharmacological Reports.
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