Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colo.
Rigel Pharmaceuticals, South San Francisco, Calif.
J Allergy Clin Immunol. 2014 Apr;133(4):1162-74. doi: 10.1016/j.jaci.2013.10.036. Epub 2013 Dec 22.
Janus kinases (JAKs) are regulators of signaling through cytokine receptors. The importance of JAK1/3 signaling on TH2 differentiation and development of lung allergic responses has not been investigated.
We sought to examine a selective JAK1/3 inhibitor (R256) on differentiation of TH subsets in vitro and on development of ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and inflammation in an experimental model of asthma.
A selective JAK1/3 inhibitor was used to assay the importance of this pathway on induction of TH1, TH2, and TH17 differentiation in vitro. In vivo, the effects of inhibiting JAK1/3 signaling were examined by administering the inhibitor during the sensitization or allergen challenge phases in the primary challenge model or just before provocative challenge in the secondary challenge model. Airway inflammation and AHR were examined after the last airway challenge.
In vitro, R256 inhibited differentiation of TH2 but not TH1 or TH17 cells, which was associated with downregulation of signal transducer and activator of transcription (STAT) 6 and STAT5 phosphorylation. However, once polarized, TH2 cells were unaffected by the inhibitor. In vivo, R256 administered during the OVA sensitization phase prevented the development of AHR, airway eosinophilia, mucus hypersecretion, and TH2 cytokine production without changes in TH1 and TH17 cytokine levels, indicating that selective blockade of TH2 differentiation was critical. Inhibitor administration after OVA sensitization but during the challenge phases in the primary or secondary challenge models similarly suppressed AHR, airway eosinophilia, and mucus hypersecretion without any reduction in TH2 cytokine production, suggesting the inhibitory effects were downstream of TH2 cytokine receptor signaling pathways.
Targeting the TH2-dependent JAK/STAT activation pathway represents a novel therapeutic approach for the treatment of asthma.
Janus 激酶（JAKs）是细胞因子受体信号转导的调节剂。JAK1/3 信号在 TH2 分化和肺部过敏反应发展中的重要性尚未得到研究。
我们试图研究一种选择性 JAK1/3 抑制剂（R256）在体外 TH 细胞亚群分化以及卵清蛋白（OVA）诱导的气道高反应性（AHR）和哮喘实验模型中炎症发展中的作用。
使用选择性 JAK1/3 抑制剂检测该途径对体外 TH1、TH2 和 TH17 分化诱导的重要性。在体内，通过在初次激发模型中的致敏或激发阶段或在二次激发模型中的激发前阶段给予抑制剂，研究抑制 JAK1/3 信号转导的作用。在最后一次气道激发后检查气道炎症和 AHR。
体外，R256 抑制 TH2 但不抑制 TH1 或 TH17 细胞的分化，这与信号转导和转录激活因子（STAT）6 和 STAT5 磷酸化的下调有关。然而，一旦极化，TH2 细胞不受抑制剂的影响。在体内，R256 在 OVA 致敏阶段给药可防止 AHR、气道嗜酸性粒细胞增多、粘液分泌过度和 TH2 细胞因子产生，而不改变 TH1 和 TH17 细胞因子水平，表明选择性阻断 TH2 分化是关键的。在初次或二次激发模型中的激发阶段给予抑制剂后，同样抑制 AHR、气道嗜酸性粒细胞增多和粘液分泌过度，但不减少 TH2 细胞因子的产生，表明抑制作用发生在 TH2 细胞因子受体信号通路的下游。
靶向 TH2 依赖性 JAK/STAT 激活途径代表了治疗哮喘的一种新的治疗方法。
