The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages
The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages
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DOI：
10.4049/jimmunol.1601330
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发表时间：
2017-05-01
影响因子：
4.4
通讯作者：
Bozec, Aline
中科院分区：
文献类型：
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作者：
Hannemann, Nicole;Jordan, Jutta;Bozec, Aline
促炎症巨噬细胞的激活与类风湿关节炎的炎症状态有关。它们的极化和激活受转录因子如核因子-kappaB和AP-1转录因子成员c-Fos的控制。令人惊讶的是，人们对AP-1转录因子c-jun在巨噬细胞激活中的作用知之甚少。在这项研究中，我们发现在促炎或抗炎刺激后，巨噬细胞中c-jun的mRNA和蛋白水平增加。基因本体论和京都基因和基因组路径百科全书使用野生型和c-jun缺失的巨噬细胞对微阵列数据进行的聚类分析强调了c-jun在巨噬细胞中的中心功能，特别是在免疫反应、IL产生和低氧途径方面。巨噬细胞中c-jun缺乏的小鼠在血清诱导的关节炎模型中表现出炎症和骨破坏的改善。体内和体外的基因图谱以及巨噬细胞的染色质免疫沉淀分析表明，c-jun直接激活了前炎症因子环氧合酶-2，间接抑制了抗炎因子精氨酸酶-1。因此，c-jun通过差异性调节环氧合酶-2和精氨酸酶-1的水平来调节巨噬细胞的激活状态，从而促进关节炎的发生。
Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-kappa B and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the antiinflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels.