Ashino Shigeru, Wakita Daiko, Zhang Yue, Chamoto Kenji, Kitamura Hidemitsu, Nishimura Takashi
Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Int Immunol. 2008 Feb;20(2):259-66. doi: 10.1093/intimm/dxm138. Epub 2007 Dec 21.
Allergic airway inflammation is one of the most typical characteristic features of bronchial asthma. T(h)2 cells, which produce IL-4, IL-5 and IL-13, are well known as major effector lymphocytes of the inflammation. In the present work, we found that subcutaneous injection of Toll-like receptor-9-ligand, CpG-oligodeoxynucleotides (CpG-ODN), remarkably suppressed eosinophilia and mucus hyper-production in T(h)2 cell-dependent airway inflammation model at the effector phase. The injection of CpG-ODN significantly blocked T(h)2 cell migration into lung. The inhibitory effects of CpG-ODN were observed even when IFN-gamma-deficient T(h)2 cells were transferred into IFN-gamma(-/-) mice. In contrast, the administration of neutralizing mAbs against type I cytokines such as IFN-alpha, IFN-beta and IL-12 significantly suppressed the inhibitory effect of CpG-ODN on airway inflammation and T(h)2 cell migration into the lung. We further demonstrated that the production of T(h)2 chemokines, thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), was significantly reduced by the CpG-ODN. The reduction of both TARC and MDC was also inhibited by the blockade of IFN-alpha, IFN-beta and IL-12 with mAbs. Thus, we revealed here that IFN-alpha, IFN-beta and IL-12, but not IFN-gamma, were required for the inhibitory effect of CpG-ODN in T(h)2 cell-mediated allergic airway inflammation. The present evidence strongly suggest that induction of type I cytokines would be promising therapeutic targets in T(h)2-dependent allergic diseases such as bronchial asthma.
过敏性气道炎症是支气管哮喘最典型的特征之一。产生白细胞介素-4、白细胞介素-5和白细胞介素-13的辅助性T细胞2（Th2）是这种炎症的主要效应淋巴细胞。在本研究中，我们发现皮下注射Toll样受体9配体——CpG寡脱氧核苷酸（CpG-ODN），在效应阶段能显著抑制Th2细胞依赖性气道炎症模型中的嗜酸性粒细胞增多和黏液过度分泌。注射CpG-ODN能显著阻止Th2细胞向肺部迁移。即使将干扰素-γ缺陷的Th2细胞转移到干扰素-γ基因敲除（IFN-γ-/-）小鼠体内，也能观察到CpG-ODN的抑制作用。相反，给予针对I型细胞因子（如干扰素-α、干扰素-β和白细胞介素-12）的中和单克隆抗体，能显著抑制CpG-ODN对气道炎症和Th2细胞向肺部迁移的抑制作用。我们进一步证明，CpG-ODN能显著降低Th2趋化因子——胸腺和活化调节趋化因子（TARC）和巨噬细胞衍生趋化因子（MDC）的产生。用单克隆抗体阻断干扰素-α、干扰素-β和白细胞介素-12也能抑制TARC和MDC的减少。因此，我们在此揭示，在Th2细胞介导的过敏性气道炎症中，CpG-ODN的抑制作用需要干扰素-α、干扰素-β和白细胞介素-12，但不需要干扰素-γ。目前的证据有力地表明，诱导I型细胞因子可能是支气管哮喘等Th2依赖性过敏性疾病有前景的治疗靶点。
