Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibitors.
Tofacitinib regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation and induction of negative feedback inhibitors.
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DOI：
10.1136/annrheumdis-2014-207201
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发表时间：
2016-01
影响因子：
27.4
通讯作者：
Fearon U
中科院分区：
文献类型：
--
作者：
Gao W;McGarry T;Orr C;McCormick J;Veale DJ;Fearon U
银屑病关节炎（PsA）是一种慢性炎症性疾病，其特征在于滑膜炎和关节软骨/骨的破坏。JAK-STAT信号通路参与PsA的发病机制。检查托法替尼（JAK抑制剂）对PsA促炎机制的影响。用托法替尼（1 µM）培养原代PsA滑膜成纤维细胞（PsAFLS）和离体PsA滑膜外植体。 Western blot法检测磷酸化STAT 3（pSTAT 3）、磷酸化STAT 1（pSTAT 1）、细胞因子信号转导抑制因子3（SOCS 3）、活化的STAT 3蛋白抑制因子3（PIAS 3）和核因子κ B细胞（NFκ Bp 65）的表达。通过侵袭/迁移试验和酶谱法定量托法替尼对PsAFLS迁移、侵袭、基质胶网络形成和基质金属肽酶（MMP）2/9的影响。ELISA法检测白细胞介素（IL）-6、IL-8、IFN-γ诱导蛋白10（IP-10）、单核细胞趋化蛋白（MCP）-1、IL-17、IL-10、MMP 3和金属蛋白酶组织抑制剂3（TIMP 3）。托法替尼显著降低PsAFLS和滑膜外植体培养物中pSTAT 3、pSTAT 1、NFκ Bp 65的表达，并诱导SOCS 3和PIAS 3的表达（p<0.05）。在功能上，托法替尼抑制PsAFLS侵袭、网络形成和迁移（所有p<0.05）。在PsA外植体中，托法替尼显著降低了IL-6、IL-8、MCP-1、MMP 9/MMP 2、MMP 3的自发分泌（均p<0.05），并降低了MMP 3/TIMP 3比值（p<0.05），对IP-10或IL-10无影响。该研究进一步支持JAK-STAT抑制作为治疗PsA的治疗靶点。
Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterised by synovitis and destruction of articular cartilage/bone. Janus-kinase and signal transducer and activator of transcription (JAK-STAT) signalling pathway is implicated in the pathogenesis of PsA. To examine the effect of tofacitinib (JAK inhibitor) on proinflammatory mechanisms in PsA. Primary PsA synovial fibroblasts (PsAFLS) and ex vivo PsA synovial explants were cultured with tofacitinib (1 µM). PhosphoSTAT3 (pSTAT3), phosphoSTAT1 (pSTAT1), suppressor of cytokine signaling-3 (SOCS3), protein inhibitor of activated Stat3 (PIAS3) and nuclear factor kappa B cells (NFκBp65) were quantified by western blot. The effect of tofacitinib on PsAFLS migration, invasion, Matrigel network formation and matrix metallopeptidase (MMP)2/9 was quantified by invasion/migration assays and zymography. Interleukin (IL)-6, IL-8, IFN-gamma-inducible protein 10 (IP-10) monocyte chemoattractant protein (MCP)-1, IL-17, IL-10, MMP3 and tissue inhibitor of metalloproteinases 3 (TIMP3) were assessed by ELISA. Tofacitinib significantly decreased pSTAT3, pSTAT1, NFκBp65 and induced SOCS3 and PIAS3 expression in PsAFLS and synovial explant cultures (p<0.05). Functionally, PsAFLS invasion, network formation and migration were inhibited by tofacitinib (all p<0.05). In PsA explant, tofacitinib significantly decreased spontaneous secretion of IL-6, IL-8, MCP-1, MMP9/MMP2, MMP3 (all p<0.05) and decreased the MMP3/TIMP3 ratio (p<0.05), with no effect observed for IP-10 or IL-10. This study further supports JAK-STAT inhibition as a therapeutic target for the treatment of PsA.