Department of Rheumatology and Inflammation Research, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden.
PLoS One. 2012;7(10):e47668. doi: 10.1371/journal.pone.0047668. Epub 2012 Oct 17.
Survivin is known as an inhibitor of apoptosis and a positive regulator of cell division. We have recently identified survivin as a predictor of joint destruction in patients with rheumatoid arthritis (RA). Flt3 ligand (Flt3L) is expressed in the inflamed joints and has adjuvant properties in arthritis. Studies on 90 RA patients (median age 60.5 years [range, 24-87], disease duration 10.5 years [range, 0-35]) show a strong positive association between the levels of survivin and Flt3L in blood. Here, we present experimental evidence connecting survivin and Flt3L signaling. Treatment of BALB/c mice with Flt3L led to an increase of survivin in the bone marrow and in splenic dendritic cells. Flt3L changed the profile of survivin splice variants, increasing transcription of the short survivin40 in the bone marrow. Treatment with an Flt3 inhibitor reduced total survivin expression in bone marrow and in the dendritic cell population in spleen. Inhibition of survivin transcription in mice, by shRNA lentiviral constructs, reduced the gene expression of Flt3L. We conclude that expression of survivin is a downstream event of Flt3 signaling, which serves as an essential mechanism supporting survival of leukocytes during their differentiation, and maturation of dendritic cells, in RA.
存活素是凋亡抑制剂和细胞分裂的正调节剂。我们最近发现存活素可作为类风湿关节炎（RA）患者关节破坏的预测因子。Flt3 配体（Flt3L）在炎症关节中表达，并具有关节炎的佐剂特性。对 90 例 RA 患者（中位年龄 60.5 岁[范围，24-87]，病程 10.5 年[范围，0-35]）的研究表明，血液中存活素和 Flt3L 水平之间存在强烈的正相关。在这里，我们提出了连接存活素和 Flt3L 信号的实验证据。用 Flt3L 治疗 BALB/c 小鼠导致骨髓和脾树突状细胞中存活素增加。Flt3L 改变了存活素剪接变体的特征，增加了骨髓中短存活素 40 的转录。用 Flt3 抑制剂治疗可减少骨髓中和脾树突状细胞群中的总存活素表达。用 shRNA 慢病毒构建体抑制小鼠中的存活素转录，可降低 Flt3L 的基因表达。我们的结论是，存活素的表达是 Flt3 信号的下游事件，该信号是在 RA 期间支持白细胞分化和树突状细胞成熟过程中存活所必需的机制。
