Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.
Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
Sci Signal. 2015 Dec 1;8(405):ra122. doi: 10.1126/scisignal.aab0949.
Interleukin-2 (IL-2)-inducible T cell kinase (ITK) mediates T cell receptor (TCR) signaling primarily to stimulate the production of cytokines, such as IL-4, IL-5, and IL-13, from T helper 2 (TH2) cells. Compared to wild-type mice, ITK knockout mice are resistant to asthma and exhibit reduced lung inflammation and decreased amounts of TH2-type cytokines in the bronchoalveolar lavage fluid. We found that a small-molecule selective inhibitor of ITK blocked TCR-mediated signaling in cultured TH2 cells, including the tyrosine phosphorylation of phospholipase C-γ1 (PLC-γ1) and the secretion of IL-2 and TH2-type cytokines. Unexpectedly, inhibition of the kinase activity of ITK during or after antigen rechallenge in an ovalbumin-induced mouse model of asthma failed to reduce airway hyperresponsiveness and inflammation. Rather, in mice, pharmacological inhibition of ITK resulted in T cell hyperplasia and the increased production of TH2-type cytokines. Thus, our studies predict that inhibition of the kinase activity of ITK may not be therapeutic in patients with asthma.
白细胞介素-2（IL-2）诱导的 T 细胞激酶（ITK）主要通过 T 细胞受体（TCR）信号传导来刺激 T 辅助 2（TH2）细胞产生细胞因子，如 IL-4、IL-5 和 IL-13。与野生型小鼠相比，ITK 基因敲除小鼠对哮喘具有抗性，并且在支气管肺泡灌洗液中表现出炎症减轻和 TH2 型细胞因子减少。我们发现，一种 ITK 的小分子选择性抑制剂可阻断培养的 TH2 细胞中的 TCR 介导的信号传导，包括 PLC-γ1（PLC-γ1）的酪氨酸磷酸化和 IL-2 和 TH2 型细胞因子的分泌。出乎意料的是，在卵清蛋白诱导的哮喘小鼠模型中，在抗原再次攻击期间或之后抑制 ITK 的激酶活性并不能减轻气道高反应性和炎症。相反，在小鼠中，ITK 的药理学抑制导致 T 细胞增生和 TH2 型细胞因子的产生增加。因此，我们的研究预测，抑制 ITK 的激酶活性在哮喘患者中可能没有治疗作用。
