Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis
Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis
复制标题
活化 STAT3 的蛋白抑制剂调节类风湿关节炎中成纤维样滑膜细胞的迁移、侵袭和活化
DOI：
10.4049/jimmunol.1403254
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发表时间：
2016-01-15
影响因子：
4.4
通讯作者：
Xu, Hanshi
中科院分区：
文献类型：
--
作者：
Lao, Minxi;Shi, Maohua;Xu, Hanshi
成纤维细胞样滑膜细胞（FLS）表现出的侵袭性表型是类风湿关节炎（RA）软骨破坏的关键因素。FLS迁移增加和随后的细胞外基质降解是RA病理学的关键。活化的STAT蛋白抑制剂（皮亚斯）家族成员包括PIAS 1、PIAS 2（PIASx）、PIAS 3和PIAS 4（PIASy），在调节多种细胞事件中发挥重要作用，如细胞存活、迁移和许多细胞类型的信号转导。然而，皮亚斯蛋白是否在RA的发病机制中起作用尚不清楚。在这项研究中，我们评估了皮亚斯蛋白在类风湿关节炎中FLS迁移、侵袭和基质金属蛋白酶（MMPs）表达中的作用。我们观察到PIAS 3的表达增加，但PIAS 1，PIAS 2，或PIAS 4，在FLS和滑膜组织与RA患者。我们发现，通过短发夹RNA敲低PIAS 3可降低FLS的迁移、侵袭和MMP-3、MMP-9和MMP-13的表达。此外，我们证明了PIAS 3在细胞迁移过程中调节板状伪足的形成。为了深入了解分子机制，我们评估了PIAS 3敲低对Rac 1/PAK 1和JNK激活的影响。我们的研究结果表明，PIAS 3介导的SUMO化的Rac 1控制其激活和调节Rac 1的下游活性的PAK 1和JNK。此外，Rac 1，PAK 1或JNK的抑制降低了RA FLS的迁移和侵袭。因此，我们的观察结果表明，PIAS 3抑制可能是通过调节滑膜细胞的迁移，入侵和激活保护关节破坏RA。
The aggressive phenotype displayed by fibroblast-like synoviocytes (FLSs) is a critical factor of cartilage destruction in rheumatoid arthritis (RA). Increased FLSs migration and subsequent degradation of the extracellular matrix are essential to the pathology of RA. Protein inhibitor of activated STAT (PIAS), whose family members include PIAS1, PIAS2 (PIASx), PIAS3, and PIAS4 (PIASy), play important roles in regulating various cellular events, such as cell survival, migration, and signal transduction in many cell types. However, whether PIAS proteins have a role in the pathogenesis of RA is unclear. In this study, we evaluated the role of PIAS proteins in FLSs migration, invasion, and matrix metalloproteinases (MMPs) expression in RA. We observed increased expression of PIAS3, but not PIAS1, PIAS2, or PIAS4, in FLSs and synovial tissues from patients with RA. We found that PIAS3 knockdown by short hairpin RNA reduced migration, invasion, and MMP-3, MMP-9, and MMP-13 expression in FLSs. In addition, we demonstrated that PIAS3 regulated lamellipodium formation during cell migration. To gain insight into molecular mechanisms, we evaluated the effect of PIAS3 knockdown on Rac1/PAK1 and JNK activation. Our results indicated that PIAS3-mediated SUMOylation of Rac1 controlled its activation and modulated the Rac1 downstream activity of PAK1 and JNK. Furthermore, inhibition of Rac1, PAK1, or JNK decreased migration and invasion of RA FLSs. Thus, our observations suggest that PIAS3 suppression may be protective against joint destruction in RA by regulating synoviocyte migration, invasion, and activation.