培非替尼通过抑制 PDGF 和 VEGF 信号通路以及 JAK，抑制成纤维样滑膜细胞的激活和血管生成的血管内皮管状结构形成。
Peficitinib inhibits fibroblast-like synoviocyte activation and angiogenic vascular endothelial tube formation via inhibitory effects on PDGF and VEGF signaling in addition to JAK.
机构信息
Pharmacology Research Labs., Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.
Pharmacology Research Labs., Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.
出版信息
J Pharmacol Sci. 2022 Oct;150(2):74-80. doi: 10.1016/j.jphs.2022.07.002. Epub 2022 Jul 31.
PURPOSE
Peficitinib and tofacitinib are known to suppress inflammation in rheumatoid arthritis (RA) by inhibiting Janus kinases (JAKs). However, these effects on tyrosine kinases other than JAKs have not yet been well investigated. We evaluated the effects of peficitinib and tofacitinib on platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptor tyrosine kinases (RTKs) and on the activation of fibroblast-like synoviocytes (FLSs) and endothelial cells, main pathological causes of RA.
METHODS
Peficitinib and tofacitinib were tested in PDGF and VEGF RTK assays. We then used FLSs derived from RA patient (RA-FLSs) and human umbilical vein endothelial cells (HUVECs) to study the effects of peficitinib and tofacitinib on PDGF- and VEGF-induced signal transduction and on the activation of RA-FLSs and endothelial cell tube formation.
FINDINGS
Peficitinib, not tofacitinib, inhibited both PDGF and VEGF RTKs in addition to JAKs in cell-free assay system. Peficitinib and tofacitinib attenuated PDGF- and VEGF-induced intracellular signal transduction pathways in RA-FLSs and HUVECs to varying degrees. Only peficitinib potently inhibited PDGF-induced secretion of interleukin-6, VEGF, and matrix metalloproteinase-3 in RA-FLSs, and endothelial cell tube formation by HUVECs.
CONCLUSION
Peficitinib may improve RA through inhibition of PDGF and VEGF signal transduction, in addition to JAK inhibition.
目的
培非替尼和托法替尼通过抑制 Janus 激酶（JAK）已知可抑制类风湿关节炎（RA）的炎症。然而，这些对除 JAK 以外的酪氨酸激酶的影响尚未得到很好的研究。我们评估了培非替尼和托法替尼对血小板衍生生长因子（PDGF）和血管内皮生长因子（VEGF）受体酪氨酸激酶（RTKs）的影响，以及对 RA 主要病理原因的成纤维样滑膜细胞（FLSs）和内皮细胞的激活的影响。
方法
在 PDGF 和 VEGF RTK 测定中测试了培非替尼和托法替尼。然后，我们使用源自 RA 患者的成纤维样滑膜细胞（RA-FLSs）和人脐静脉内皮细胞（HUVECs）来研究培非替尼和托法替尼对 PDGF 和 VEGF 诱导的信号转导以及对 RA-FLSs 和内皮细胞管形成的激活的影响。
发现
在无细胞测定系统中，培非替尼而非托法替尼除了抑制 JAK 外，还抑制了 PDGF 和 VEGF RTKs。培非替尼和托法替尼在 RA-FLSs 和 HUVECs 中不同程度地减弱了 PDGF 和 VEGF 诱导的细胞内信号转导途径。只有培非替尼能有效抑制 PDGF 诱导的 RA-FLSs 中白细胞介素-6、VEGF 和基质金属蛋白酶-3 的分泌，以及 HUVECs 的内皮细胞管形成。
结论
除抑制 JAK 外，培非替尼可能通过抑制 PDGF 和 VEGF 信号转导来改善 RA。
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