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Polyene phosphatidylcholine ameliorates synovial inflammation: involvement of PTEN elevation and glycolysis suppression

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Abstract

Background

Synovial inflammation, characterized by the activation of synovial fibroblasts (SFs), is a crucial factor to drive the progression of rheumatoid arthritis (RA). Polyene phosphatidylcholine (PPC), the classic hepatoprotective drug, has been reported to ameliorate arthritis in animals. However, the molecular mechanism remains poorly understood.

Methods and results

Using in vitro primary synovial fibroblast (SFs) culture system, we revealed that phosphatase and tension homolog deleted on chromosome 10 (PTEN), a tumor suppressor, mediates the anti-inflammatory effect of PPC in lipopolysaccharide (LPS)-stimulated primary SFs. PPC decreased the production of TNF-α and IL-6 production while elevating the level of IL-10 and TGF-β. Furthermore, PPC up-regulated the expression of PTEN, but inhibited the expression of p-AKT (ser473) and PI3K-p85α. Moreover, pre-treatment of SF1670 (the inhibitor of PTEN) or 740Y-P (the agonist of AKT/PI3K pathways) partially abrogated the anti-inflammatory effect of PPC. In addition, PPC could inhibit the expression of GLUT4, a key transporter of glucose that fuels the glycolysis, which is accompanied by the expression downregualtion of glycolytic enzymes PFKFB3 and PKM2. Furthermore, PPC could reduce ROS production and mitochondrial membrane potential in LPS-stimulated SFs and MH7A cell line.

Conclusion

The present study supported that PPC can alleviate synovial inflammation, which involves in the elevation of PTEN and blockage of glycolysis.

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Funding

This work was supported by grants from the Starting Foundation for Talents of Xuzhou Medical College (No. D2015004), the Natural Science Foundation of the Jiangsu Higher Education Institutions (No. 15KJB310025), the Jiangsu Qinglan Project, and the Liangshan Research Project (2021). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. Fenfen Sun, Wenting Hao and Xianran Meng share first authorship on this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogen Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu, China

    Fenfen Sun, Wenting Hao, Xianran Meng, Daxiang Xu, Xiangyang Li, Kuiyang Zheng, Yinghua Yu & Wei Pan

  2. National Experimental Teaching Demonstration Center of Basic Medicine (Xuzhou Medical University), Xuzhou, Jiangsu, China

    Fenfen Sun

  3. Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, China

    Wenting Hao

  4. Liangshan College (Li Shui) China, Lishui University, Lishui, Zhejiang, China

    Dahui Wang

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  1. Fenfen Sun
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Contributions

Conceived and designed the experiments: WP, DHW, YHY, KYZ. Performed the experiments: FFS, WTH, XRM. Analyzed the data: FFS, WTH, XRM, XYL. Contributed reagents/materials/analysis tools: WP, DHW. Wrote the manuscript: FFS, WP. All authors have read and approved the manuscript.

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Correspondence to Dahui Wang or Wei Pan.

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This study was approved by the Ethics Committee of Xuzhou Medical University (Xuzhou, China, SYXK (Su) 2015-0009). All animal care and experiments were performed in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the Ministry of Health (China).

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11033_2022_8043_MOESM1_ESM.jpg

Supplementary Fig. 1 PPC does not significantly affect the normal proliferation of SFs. SFs were prepared from the joint of C57BL/6J mice. CCK-8 assay was used to determine the proliferative profile of 24 h (A) and 48 h (B) post mentioned concentration of PPC. Supplementary material 1 (JPG 46.6 kb)

11033_2022_8043_MOESM2_ESM.jpg

Supplementary Fig. 2 PPC decreases the mitochondrial membrane potential and ROS production in SFs. Primary SFs cells were stimulated with PPC (20 µg/ml) with or without LPS (100 ng/ml) for 24 h. The cells were collected to determine the mitochondrial membrane potential and ROS production by Mitochondrial membrane potential assay kit (A) and Reactive Oxygen Species Assay Kit (B), respectively. The ROS (C) and mitochondrial membrane potential (D) were determined in the MH7A cell line treated with PPC (20 µg/ml) for 24 h using the colorimetric assay. **P < 0.01, ***P < 0.001. Supplementary material 2 (JPG 75.8 kb)

11033_2022_8043_MOESM3_ESM.jpg

Supplementary Fig. 3 SF1670 with indicated concentrations does not affect the proliferation and migration of normal SFs. (A) the effect of SF1670 pretreatment on the proliferative profile of SFs in the presence of PPC determined by CCK-8 assay, (B) the migratory profile of SFs after exposure to SF1670 evaluated by wound-healing assay. Supplementary material 3 (JPG 139.9 kb)

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Sun, F., Hao, W., Meng, X. et al. Polyene phosphatidylcholine ameliorates synovial inflammation: involvement of PTEN elevation and glycolysis suppression. Mol Biol Rep 50, 687–696 (2023). https://doi.org/10.1007/s11033-022-08043-3

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