托法替尼
自噬
银屑病性关节炎
调制(音乐)
医学
成纤维细胞
功能(生物学)
癌症研究
化学
类风湿性关节炎
药理学
细胞生物学
生物
内科学
细胞凋亡
生物化学
物理
声学
体外
作者
Ettore Silvagni,Sonia Missiroli,Simone Patergnani,Caterina Boncompagni,Clotilde D'Ugo,Carlo Garaffoni,Maria Sofia Ciliento,Giovanni Lanza,Massimo Bonora,Roberta Gafà,Mariasole Perrone,Alessandra Bortoluzzi,Carlotta Giorgi,Marcello Govoni,Ca Scirè,Paolo Pinton
标识
DOI:10.1016/j.jaut.2023.103159
摘要
To evaluate the in vitro effect of tofacitinib on autophagy activity of psoriatic arthritis (PsA) fibroblast-like synoviocytes (FLS), and to confirm its activity on inflammatory and invasive properties of FLS and synovial cells, deepening the impact on mitochondrial function. FLS, peripheral blood mononuclear cells (PBMCs), and synovial cells from active PsA patients were cultured with tofacitinib 1 μM or vehicle control for 24 h. Autophagy was measured by Western blot and by fluorescence microscopy. Chemokines/cytokines released into culture supernatants were quantified by ELISA, while invasive properties of FLS by migration assays. Specific mitochondrial probes were adopted to measure intracellular reactive oxygen species (ROS), mitochondrial potential, morphology, turnover and mitophagy. Oxygen consumption rate (OCR), reflecting oxidative phosphorylation, was quantified using the Seahorse technology. Differences were determined by adopting the non-parametric Wilcoxon signed rank test. 18 patients with moderately-to-severely active PsA were enrolled. Tofacitinib significantly increased the levels of the autophagy markers LC3-II and ATG7 in PsA FLS compared to vehicle control, suggesting an increase in spontaneous autophagy activity; no effect was highlighted in PBMCs and synovial cells cultures. Tofacitinib reduced migration properties of PsA FLS, and reduced MCP-1 and IL-6 release into FLS and synovial cells cultures supernatants. Furthermore, tofacitinib decreased intracellular ROS production, increased basal OCR, ATP production and maximal respiratory capacity, and enhanced mitophagy and mitochondrial turnover. The JAK inhibitor tofacitinib reduces the pro-invasive and pro-inflammatory properties of PsA FLS. Autophagy induction and mitochondrial quality control modulation by tofacitinib might contribute to FLS function restoration.
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