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Anti-arthritis effect of a novel quinazoline derivative through inhibiting production of TNF-α mediated by TNF-α converting enzyme in murine collagen-induced arthritis model.

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机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China [2]Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330031, China

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关键词： TNF-a TNF-a converting enzyme Rheumatoid arthritis Collagen-induced arthritis Quinazoline

摘要：

TNF-α is a dominant inflammatory mediator in the pathogenesis of inflammatory diseases including rheumatoid arthritis. In our research, we discovered 2-chloro-N-(4-(2-morpholinoethoxy)phenyl)quinazolin-4-amine (9c) exhibited an outstanding anti-inflammatory activity on inhibiting TNF-α production with an IC50 of 8.86 μM in RAW264.7 cells. Interestingly, 9c had no effect on mRNA level of TNF-α but up-regulated the precursor of TNF-α (pro-TNF-α). Then, we studied TNF-α converting enzyme (TACE), which is the most important proteases responsible for the release of TNF-α from pro-TNF-α to soluble TNF-α. The results showed 9c reduced TACE both on the levels of mRNA and protein in a dose-dependent manner. In vivo study, collagen-induced arthritis (CIA) mice were treated by 9c orally. 9c exhibited significant anti-arthritis effect by ameliorating arthritic score, reducing inflammatory cell infiltration, protecting joints from destruction and decreasing the production of systemic TNF-α, IL-6, IL-1β. The underlying mechanism of 9c on CIA was coincided with the in vitro, which was mediated by TACE. In conclusion, we discovered a novel quinazoline derivative which ameliorates arthritis through inhibiting production of TNF-α mediated by TACE for the first time. Copyright © 2015 Elsevier Inc. All rights reserved.

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出版当年[2015]版：

大类 | 3 区生物

小类 | 4 区生化与分子生物学 4 区生物物理

最新[2023]版：

大类 | 3 区生物学

小类 | 3 区生物物理 4 区生化与分子生物学

第一作者：

第一作者机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China

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通讯作者：

通讯机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041, China [*1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Keyuan Road 4, Gaopeng Street, Chengdu, Sichuan 610041, China.

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Anti-arthritis effect of a novel quinazoline derivative through inhibiting production of TNF-α mediated by TNF-α converting enzyme in murine collagen-induced arthritis model.

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