Hannemann Nicole, Jordan Jutta, Paul Sushmita, Reid Stephen, Baenkler Hanns-Wolf, Sonnewald Sophia, Bäuerle Tobias, Vera Julio, Schett Georg, Bozec Aline
Department of Internal Medicine 3-Rheumatology and Immunology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany.
Preclinical Imaging Platform Erlangen, Institute of Radiology, University Hospital Erlangen, 91054 Erlangen, Germany.
J Immunol. 2017 May 1;198(9):3605-3614. doi: 10.4049/jimmunol.1601330. Epub 2017 Mar 15.
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-κB 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 anti-inflammatory 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.
促炎巨噬细胞的激活与类风湿性关节炎的炎症状态相关。它们的极化和激活受转录因子如核因子κB（NF-κB）和AP-1转录因子成员c-Fos的控制。令人惊讶的是，关于AP-1转录因子c-Jun在巨噬细胞激活中的作用知之甚少。在本研究中，我们发现促炎或抗炎刺激后巨噬细胞中c-Jun的mRNA和蛋白质水平升高。使用野生型和c-Jun缺失的巨噬细胞对微阵列数据进行基因本体论和京都基因与基因组百科全书通路富集聚类分析，突出了c-Jun在巨噬细胞中的核心功能，特别是在免疫反应、白细胞介素产生和缺氧通路方面。巨噬细胞中缺乏c-Jun的小鼠在血清诱导的关节炎模型中炎症和骨破坏有所改善。体内和体外基因分析，以及巨噬细胞的染色质免疫沉淀分析，揭示了c-Jun对促炎因子环氧合酶-2的直接激活和对抗炎因子精氨酸酶-1的间接抑制。因此，c-Jun通过差异调节环氧合酶-2和精氨酸酶-1的水平来调节巨噬细胞的激活状态并促进关节炎。
