Messemaker T C, Mikkers H M M, Huizinga T W, Toes R E M, van der Helm-van Mil A H M, Kurreeman F
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
Genes Immun. 2017 Sep;18(3):191-196. doi: 10.1038/gene.2017.20. Epub 2017 Aug 10.
Innate immune cells, such as monocytes, can adopt a long-lasting pro-inflammatory phenotype, a phenomenon called 'trained immunity'. In trained immunity, increased cytokine levels of genes, like interleukin (IL)-6 and tumor necrosis factor (TNF)-α, are observed, which are associated with increased histone 3 lysine 4 trimethylation (H3K4me3) in the promoter region. As systemic IL6 and TNFα levels are increased in rheumatoid arthritis (RA) patients and monocytes are known to be the primary producers of TNFα and IL6, we hypothesized that 'trained immunity' signals may be observed at these genes in monocytes from RA patients. CD14+ monocytes were isolated from untreated RA patients and paired age-matched healthy controls. H3K4me3, mRNA, protein and serum levels of IL6 and TNFα were evaluated by chromatin immunoprecipitation, reverse-transcription quantitative PCR and enzyme-linked immunosorbent assays. Despite elevated serum levels of TNFα and IL6 in the tested RA patients (P<0.05), ex vivo isolated monocytes displayed similar H3K4me3 levels to healthy controls in the promoter region of TNFα and IL6. Concordantly, mRNA and protein levels of IL6 and TNFα were similar before and after lipopolysaccharide stimulation between patients and controls. Together, with the current number of individuals tested we have not detected enhanced trained immunity signals in circulating monocytes from untreated RA patients, despite increased IL6 and TNFα serum levels.
诸如单核细胞等固有免疫细胞可呈现持久的促炎表型，这一现象称为“训练免疫”。在训练免疫中，可观察到白细胞介素（IL）-6和肿瘤坏死因子（TNF）-α等基因的细胞因子水平升高，这与启动子区域组蛋白3赖氨酸4三甲基化（H3K4me3）增加有关。由于类风湿关节炎（RA）患者的全身IL6和TNFα水平升高，且已知单核细胞是TNFα和IL6的主要产生者，我们推测在RA患者单核细胞的这些基因处可能观察到“训练免疫”信号。从未经治疗的RA患者和年龄匹配的健康对照者中分离出CD14+单核细胞。通过染色质免疫沉淀、逆转录定量PCR和酶联免疫吸附测定法评估H3K4me3、IL6和TNFα的mRNA、蛋白及血清水平。尽管在受试RA患者中血清TNFα和IL6水平升高（P<0.05），但体外分离的单核细胞在TNFα和IL6启动子区域的H3K4me3水平与健康对照相似。同样，患者和对照者在脂多糖刺激前后IL6和TNFα的mRNA及蛋白水平相似。尽管血清IL6和TNFα水平升高，但就目前所检测的个体数量而言，我们尚未在未经治疗的RA患者循环单核细胞中检测到增强的训练免疫信号。
