4-苯基丁酸是一种有效的内质网应激抑制剂，通过抑制滑膜成纤维细胞的增殖和炎症反应来减轻小鼠胶原诱导的关节炎的严重程度,The Kaohsiung Journal of Medical Sciences

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4-苯基丁酸是一种有效的内质网应激抑制剂，通过抑制滑膜成纤维细胞的增殖和炎症反应来减轻小鼠胶原诱导的关节炎的严重程度
The Kaohsiung Journal of Medical Sciences ( IF 2.7 ) Pub Date : 2021-03-24 , DOI: 10.1002/kjm2.12376
Yunjung Choi _{1,

2,

3} , Eun-Gyeong Lee _{2,

3} , Ji-Hyeon Jeong _{2,

3} , Wan-Hee Yoo _{1,

2,

3}

Affiliation

4-Phenylbutyric acid (4-PBA) 通过抑制内质网 (ER) 应激发挥强大的药理作用，包括抗炎特性。然而，尚不清楚 4-PBA 是否会减轻类风湿性关节炎的严重程度。本研究旨在确定 4-PBA 抑制 ER 应激是否能改善实验性关节炎。在有或没有 4-PBA 的白细胞介素 (IL)-1β 存在下评估滑膜成纤维细胞 (SF) 的增殖和基质金属蛋白酶 (MMP) 的表达。评估了 4-PBA 对 IL-1β 刺激的 SF 中丝裂原活化蛋白激酶 (MAPK) 磷酸化和核因子-κB (NF-κB) 活化的影响。在一项体内研究中，使用患有胶原诱导性关节炎 (CIA) 的 DBA/1 小鼠研究了 4-PBA 的作用。临床，对用 4-PBA 治疗的 CIA 进行组织学和血清学评估以确定 4-PBA 的治疗效果。在体外，4-PBA 通过抑制 IL-1β 刺激的 SFs 中 MAPK 和 NF-κB 的磷酸化来抑制 IL-1β 刺激的 SFs 和 MMP-1 和 MMP-3 的增殖和表达。4-PBA 治疗显着减轻了 CIA 小鼠关节炎的严重程度。4-PBA 治疗改善了关节肿胀和骨侵蚀和破坏程度，降低了炎性细胞因子和 MMP-3 和 Cox-2 的水平。此外，在 4-PBA 治疗的小鼠中，组织病理学发现有显着改善。这些发现表明，4-PBA 可以通过部分阻断 MAPKs 的磷酸化和 SFs 中 NF-κB 的激活来减轻 CIA 小鼠关节炎的严重程度。因此，

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4-Phenylbutyric acid, a potent endoplasmic reticulum stress inhibitor, attenuates the severity of collagen-induced arthritis in mice via inhibition of proliferation and inflammatory responses of synovial fibroblasts

4-Phenylbutyric acid (4-PBA) exerts potent pharmacological effects, including anti-inflammatory properties, via inhibition of endoplasmic reticulum (ER) stress. However, it is not known whether 4-PBA attenuates the severity of rheumatoid arthritis. The present study aimed to determine whether the inhibition of ER stress by 4-PBA ameliorated experimentally induced arthritis. The proliferation of synovial fibroblasts (SFs) and expression of matrix metalloproteinases (MMPs) were evaluated in the presence of interleukin (IL)-1β with or without 4-PBA. The effect of 4-PBA on the phosphorylation of Mitogen-activated protein kinase (MAPK) and the activation of Nuclear factor-κB (NF-κB) in IL-1β-stimulated SFs was assessed. In an in vivo study, the effects of 4-PBA were investigated using DBA/1 mice with collagen-induced arthritis (CIA). Clinical, histological, and serological assessments of CIA treated with 4-PBA were performed to determine the therapeutic effect of 4-PBA. In vitro, 4-PBA inhibited the proliferation and expression of IL-1β-stimulated SFs and MMP-1 and MMP-3 through the suppression of both the phosphorylation of MAPKs and NF-κB in IL-1β-stimulated SFs. The 4-PBA treatment markedly attenuated the severity of arthritis in CIA mice. The 4-PBA treatment ameliorated joint swelling and the degree of bone erosion and destruction and decreased the level of inflammatory cytokines and MMP-3 and Cox-2. Furthermore, remarkable improvements in histopathological findings occurred in 4-PBA-treated mice. These findings suggested that 4-PBA could attenuate the severity of arthritis in CIA mice by partially blocking the phosphorylation of MAPKs and the activation of NF-κB in SFs. Thus, through the inhibition of ER stress, 4-PBA may be a potent agent for the treatment of RA.

更新日期：2021-03-24

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