Kshirsagar Sudhir, Riedl Magdalena, Billing Heiko, Tönshoff Burkhard, Thangavadivel Shanmugapriya, Steuber Christian, Staude Hagen, Wechselberger Gottfried, Edelbauer Monika
Department of Pediatrics I, Innsbruck Medical University, A-6020 Innsbruck, Austria;
University Children's Hospital, Heidelberg, 69120 Heidelberg, Germany; University Children's Hospital, 72076 Tuebeingen, Germany;
J Immunol. 2014 Nov 15;193(10):4895-903. doi: 10.4049/jimmunol.1400044. Epub 2014 Oct 22.
Th17 cells infiltrate the kidneys of patients with lupus nephritis (LN) and are critical for the pathogenesis of this disease. In this study, we show that enhanced activity of Stat3 in CD4(+)CD45RA(-)Foxp3(-) and Foxp3(low) effector T cells from children with LN correlates with increased frequencies of IL-17-producing cells within these T cell populations. The levels of retinoic acid-related orphan receptor c and IL-17 mRNA are significantly higher in PBMCs from children with LN than in those from controls. Mammalian target of rapamycin inhibition by rapamycin reduces both Stat3 activation in effector T cells and the frequency of IL-17-producing T cells in lupus patients. Complement factor C5a slightly increases the expression of IL-17 and induces activation of Akt in anti-CD3-activated lupus effector T cells. Th17 cells from children with LN exhibit high Akt activity and enhanced migratory capacity. Inhibition of the Akt signaling pathway significantly decreases Th17 cell migration. These findings indicate that the Akt signaling pathway plays a significant role in the migratory activity of Th17 cells from children with LN and suggest that therapeutic modulation of the Akt activity may inhibit Th17 cell trafficking to sites of inflammation and thus suppress chronic inflammatory processes in children with LN.
辅助性T细胞17（Th17细胞）浸润狼疮性肾炎（LN）患者的肾脏，并且对该疾病的发病机制至关重要。在本研究中，我们发现，LN患儿的CD4(+)CD45RA(-)Foxp3(-)和Foxp3(low)效应T细胞中信号转导和转录激活因子3（Stat3）的活性增强，与这些T细胞群体中产生白细胞介素-17（IL-17）的细胞频率增加相关。LN患儿外周血单个核细胞（PBMCs）中维甲酸相关孤儿受体c和IL-17信使核糖核酸（mRNA）的水平显著高于对照组。雷帕霉素抑制哺乳动物雷帕霉素靶蛋白可降低狼疮患者效应T细胞中Stat3的激活以及产生IL-17的T细胞频率。补体因子C5a可略微增加IL-17的表达，并诱导抗CD3激活的狼疮效应T细胞中蛋白激酶B（Akt）的激活。LN患儿的Th17细胞表现出高Akt活性和增强的迁移能力。抑制Akt信号通路可显著降低Th17细胞迁移。这些发现表明，Akt信号通路在LN患儿Th17细胞的迁移活性中起重要作用，并提示对Akt活性的治疗性调节可能抑制Th17细胞向炎症部位的迁移，从而抑制LN患儿的慢性炎症过程。
