Shin Kihyuk, Hwang Jung Joo, Kwon Bo-In, Kheradmand Farrah, Corry David B, Lee Seung-Hyo
Cellular Immunology Laboratory, Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea.
Clin Exp Med. 2015 Aug;15(3):233-44. doi: 10.1007/s10238-014-0292-7. Epub 2014 Jun 13.
The leukotrienes (LTs) enhance allergen- and interleukin (IL)-13-dependent allergic lung inflammatory disease. However, the precise requirement of LTs and the mechanism by which they elicit allergic lung responses remain uncertain. To clarify the involvement of LTs in respiratory allergen- and IL-13-induced experimental asthma and elucidate the underlying mechanisms of LTs-mediated enhanced allergic asthma, we investigated the role of LTs in two models of allergic inflammation: intranasal Aspergillus protease allergen and recombinant IL-13-induced T helper type 2 (Th2) cell-mediated inflammation, and also examined Th2-related chemokines downstream of LTs signaling. 5-Lipoxygenase (5-LO)-deficient mice exposed to short-term intranasal Aspergillus protease allergen showed attenuated airway inflammation, decreased airway hyper-responsiveness and reduced bronchoalveolar eosinophilia when compared to wild-type mice. However, this phenotype was less apparent using long exposure to the same allergen. 5-LO-deficient mice exposed to intranasal rIL-13 also showed attenuated phenotypes of allergic asthma via significant reduction in Th2-specific chemokines, CCL7 and CCL17 production and decreased Th2 cells recruitment to the lungs. Addition of leukotriene B4 (LTB4) and LTC4 to the airways of 5-LO-deficient mice resulted in the rescue of rIL-13-induced experimental asthma. Furthermore, LTs addition to rIL-13 synergistically enhanced the production of Th2-specific chemokines in the lung and inflammatory responses. Therefore, our findings suggest that LTs complement allergens and their downstream cytokine (e.g., IL-13) induced Th2 inflammation by enhancing the induction of Th2 chemokines.
白三烯（LTs）可增强变应原和白细胞介素（IL）-13依赖性变应性肺部炎症性疾病。然而，LTs的确切需求及其引发变应性肺部反应的机制仍不明确。为了阐明LTs在呼吸道变应原和IL-13诱导的实验性哮喘中的作用，并阐明LTs介导的变应性哮喘增强的潜在机制，我们在两种变应性炎症模型中研究了LTs的作用：鼻内曲霉蛋白酶变应原和重组IL-13诱导的2型辅助性T细胞（Th2）介导的炎症，并研究了LTs信号下游与Th2相关的趋化因子。与野生型小鼠相比，短期鼻内给予曲霉蛋白酶变应原的5-脂氧合酶（5-LO）缺陷小鼠气道炎症减轻、气道高反应性降低、支气管肺泡嗜酸性粒细胞减少。然而，长期暴露于相同变应原时，这种表型不太明显。鼻内给予重组IL-13的5-LO缺陷小鼠也表现出变应性哮喘表型减轻，这是由于Th2特异性趋化因子CCL7和CCL17的产生显著减少以及Th2细胞向肺内募集减少。向5-LO缺陷小鼠气道中添加白三烯B4（LTB4）和白三烯C4（LTC4）可挽救重组IL-13诱导的实验性哮喘。此外，向重组IL-13中添加LTs可协同增强肺内Th2特异性趋化因子的产生和炎症反应。因此，我们的研究结果表明，LTs通过增强Th2趋化因子的诱导来补充变应原及其下游细胞因子（如IL-13）诱导的Th2炎症。
