Fms-Like Tyrosine Kinase 3 Ligand Decreases T Helper Type 17 Cells and Suppressors of Cytokine Signaling Proteins in the Lung of House Dust Mite-Sensitized and -Challenged Mice
Fms-Like Tyrosine Kinase 3 Ligand Decreases T Helper Type 17 Cells and Suppressors of Cytokine Signaling Proteins in the Lung of House Dust Mite-Sensitized and -Challenged Mice
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DOI：
10.1165/rcmb.2009-0241oc
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发表时间：
2010-11-01
影响因子：
6.4
通讯作者：
Agrawal, Devendra K.
中科院分区：
文献类型：
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作者：
McGee, Halvor S.;Stallworth, Arthur L.;Agrawal, Devendra K.
我们以前报道过Fms样酪氨酸激酶3配体（Flt 3-L）逆转气道高反应性（AHR）和气道炎症，并增加变应原致敏和激发小鼠肺中调节性CD 11 c（高）CD 8 α（高）CD 11b（低）树突状细胞和CD 4（+）CD 25（+）ICOS（+）Foxp 3（+）IL-10（+）T调节细胞的数量。在这项研究中，我们评估了Flt 3-L对屋尘螨（HDM）致敏和攻击小鼠肺中Th 17细胞和细胞因子信号转导抑制因子（SOCS）蛋白表达的影响。用HDM致敏BALB/c小鼠，建立乙酰甲胆碱的AHR。每天用Flt 3-L（5 μ g，腹膜内）处理小鼠10天。ELISA法检测支气管肺泡灌洗液（BALF）中IL-4、IL-5、IL-6、IL-8、IL-13和转化生长因子（TGF）-β的水平。Flt 3-L治疗逆转了现有的乙酰甲胆碱AHR，并显著降低了BALF中的嗜酸性粒细胞、嗜中性粒细胞、IL-5、IL-6、IL-8和IL-13以及TGF-β水平。HDM致敏和激发小鼠显示肺CD 4（+）IL-17（+）IL-23 R（+）CD 25（-）T细胞显著增加，并高表达视黄酸相关孤儿受体（ROR）-γ t转录本。然而，Flt 3-L的给药显著降低了肺CD 4（+）IL-17（+）IL-23 R（+）CD 25（-）T细胞的数量，这些细胞中ROR-γ t mRNA的表达显著降低。HDM致敏导致肺中SOCS-1、-3和-5的表达显著增加。Flt 3-L处理消除了SOCS-1和SOCS-3蛋白的增加，而SOCS-5表达显著降低。这些数据表明，Flt 3-L逆转小鼠模型中过敏性哮喘特征的治疗作用是通过降低BALF中IL-6和TGF-β水平介导的，这反过来又降低了HDM致敏和激发小鼠肺中的CD 4（+）IL-17（+）IL-23 R（+）ROR-γ t（+）CD 25（-）T细胞和SOCS-1和SOCS-3的表达。
We previously reported that Fms-like tyrosine kinase 3 ligand (Flt3-L) reversed airway hyperresponsiveness (AHR) and airway inflammation, and increased the number of regulatory CD11c(high)CD8 alpha(high)CD11b(low) dendritic cells and CD4(+)CD25(+)ICOS(+)Foxp3(+)IL-10(+) T-regulatory cells in the lung of allergen-sensitized and -challenged mice. In this study, we evaluated the effect of Flt3-L on Th17 cells and expression of suppressors of cytokine signaling (SOCS) proteins in the lungs of house dust mite (HDM)-sensitized and -challenged mice. BALB/c mice were sensitized and challenged with HDM, and AHR to methacholine was established. Mice were treated with Flt3-L (5 mu g, intraperitoneal) daily for 10 days. Levels of IL-4, -5, -6, -8, and -13, and transforming growth factor (TGF)-beta in the bronchoalveolar lavage fluid (BALF) were examined by ELISA. Flt3-L treatment reversed existing AHR to methacholine and substantially decreased eosinophils, neutrophils, IL-5, -6, -8, and IL-13, and TGF-beta levels in the BALF. HDM-sensitized and -challenged mice showed a significant increase in lung CD4(+)IL-17(+)IL-23R(+)CD25(-) T cells with high expression of retinoic acid-related orphan receptor (ROR)-gamma t transcripts. However, administration of Flt3-L substantially decreased the number of lung CD4(+)IL-17(+)IL-23R(+)CD25(-) T cells, with significantly decreased expression of ROR-gamma t mRNA in these cells. HDM sensitization caused a significant increase in the expression of SOCS-1, -3, and -5 in the lung. Flt3-L treatment abolished the increase in SOCS-1 and SOCS-3 proteins, whereas SOCS-5 expression was significantly reduced. These data suggest that the therapeutic effect of Flt3-L in reversing the hallmarks of allergic asthma in a mouse model is mediated by decreasing IL-6 and TGF-beta levels in the BALF, which, in turn, decrease CD4(+)IL-17(+)IL-23R(+)ROR-gamma t(+)CD25(-) T cells and the expression of SOCS-1 and SOCS-3 in the lung of HDM-sensitized and -challenged mice.