Hsu Sheng-Min, Yang Chang-Hao, Shen Fang-Hsiu, Chen Shun-Hua, Lin Chia-Jhen, Shieh Chi-Chang
Institute of Clinical Medicine, College of Medicine, National Cheng-Kung University, No. 35, Siao-Dong Road, Tainan 70403, Taiwan ; Department of Ophthalmology, National Cheng-Kung University Hospital, Tainan 70403, Taiwan.
Department of Ophthalmology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Mediators Inflamm. 2015;2015:847373. doi: 10.1155/2015/847373. Epub 2015 Jan 12.
Bortezomib is a proteasome inhibitor used for hematologic cancer treatment. Since it can suppress NF-κB activation, which is critical for the inflammatory process, bortezomib has been found to possess anti-inflammatory activity. In this study, we evaluated the effect of bortezomib on experimental autoimmune uveitis (EAU) in mice and investigated the potential mechanisms related to NF-κB inactivation. High-dose bortezomib (0.75 mg/kg), low-dose bortezomib (0.15 mg/kg), or phosphate buffered saline was given after EAU induction. We found that the EAU is ameliorated by high-dose bortezomib treatment when compared with low-dose bortezomib or PBS treatment. The DNA-binding activity of NF-κB was suppressed and expression of several key inflammatory mediators including TNF-α, IL-1α, IL-1β, IL-12, IL-17, and MCP-1 was lowered in the high-dose bortezomib-treated group. These results suggest that proteasome inhibition is a promising treatment strategy for autoimmune uveitis.
硼替佐米是一种用于治疗血液系统癌症的蛋白酶体抑制剂。由于它能抑制对炎症过程至关重要的核因子κB（NF-κB）的激活，因此已发现硼替佐米具有抗炎活性。在本研究中，我们评估了硼替佐米对小鼠实验性自身免疫性葡萄膜炎（EAU）的影响，并研究了与NF-κB失活相关的潜在机制。在诱导EAU后给予高剂量硼替佐米（0.75毫克/千克）、低剂量硼替佐米（0.15毫克/千克）或磷酸盐缓冲盐水。我们发现，与低剂量硼替佐米或磷酸盐缓冲盐水治疗相比，高剂量硼替佐米治疗可改善EAU。在高剂量硼替佐米治疗组中，NF-κB的DNA结合活性受到抑制，包括肿瘤坏死因子-α（TNF-α）、白细胞介素-1α（IL-1α）、白细胞介素-1β（IL-1β）、白细胞介素-12（IL-12）、白细胞介素-17（IL-17）和单核细胞趋化蛋白-1（MCP-1）在内的几种关键炎症介质的表达降低。这些结果表明，蛋白酶体抑制是自身免疫性葡萄膜炎一种有前景的治疗策略。
