Auer Judith, Bläss Markus, Schulze-Koops Hendrik, Russwurm Stefan, Nagel Thomas, Kalden Joachim R, Röllinghoff Martin, Beuscher Horst Ulrich
Institute for Clinical Microbiology, Immunology and Hygiene, University of Erlangen-Nuremberg, Wasserturmstrasse 3-5, D-91054 Erlangen, Germany.
Arthritis Res Ther. 2007;9(5):R94. doi: 10.1186/ar2294.
Rheumatoid arthritis (RA) is characterized by the recruitment of leukocytes and the accumulation of inflammatory mediators within the synovial compartment. Release of the chemokine CCL18 has been widely attributed to antigen-presenting cells, including macrophages and dendritic cells. This study investigates the production of CCL18 in polymorphonuclear neutrophils (PMN), the predominant cell type recruited into synovial fluid (SF). Microarray analysis, semiquantitative and quantitative reverse transcriptase polymerase chain reaction identified SF PMN from patients with RA as a novel source for CCL18 in diseased joints. Highly upregulated expression of other chemokine genes was observed for CCL3, CXCL8 and CXCL10, whereas CCL21 was downregulated. The chemokine receptor genes were differentially expressed, with upregulation of CXCR4, CCRL2 and CCR5 and downregulation of CXCR1 and CXCR2. In cell culture experiments, expression of CCL18 mRNA in blood PMN was induced by tumor necrosis factor alpha, whereas synthesis of CCL18 protein required additional stimulation with a combination of IL-10 and vitamin D3. In comparison, recruited SF PMN from patients with RA were sensitized for CCL18 production, because IL-10 alone was sufficient to induce CCL18 release. These results suggest a release of the T cell-attracting CCL18 by PMN when recruited to diseased joints. However, its production is tightly regulated at the levels of mRNA expression and protein synthesis.
类风湿性关节炎（RA）的特征在于白细胞的募集以及滑膜腔内炎症介质的积累。趋化因子CCL18的释放一直被广泛认为是由抗原呈递细胞产生的，包括巨噬细胞和树突状细胞。本研究调查了多形核中性粒细胞（PMN）中CCL18的产生情况，PMN是募集到滑液（SF）中的主要细胞类型。微阵列分析、半定量和定量逆转录聚合酶链反应确定，来自RA患者的SF PMN是患病关节中CCL18的一种新来源。观察到CCL3、CXCL8和CXCL10的其他趋化因子基因表达高度上调，而CCL21表达下调。趋化因子受体基因表达存在差异，CXCR4、CCRL2和CCR5上调，而CXCR1和CXCR2下调。在细胞培养实验中，肿瘤坏死因子α可诱导血液PMN中CCL18 mRNA的表达，而CCL18蛋白的合成则需要IL-10和维生素D3联合给予额外刺激。相比之下，来自RA患者的募集到的SF PMN对CCL18的产生更为敏感，因为单独的IL-10就足以诱导CCL18释放。这些结果表明，PMN募集到患病关节时会释放吸引T细胞的CCL18。然而，其产生在mRNA表达和蛋白质合成水平受到严格调控。
