Matsubara Shigeki, Takeda Katsuyuki, Kodama Taku, Joetham Anthony, Miyahara Nobuaki, Koya Toshiyuki, Swasey Christina H, Okamoto Masakazu, Dakhama Azzeddine, Gelfand Erwin W
Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Am J Respir Cell Mol Biol. 2007 Mar;36(3):324-32. doi: 10.1165/rcmb.2006-0231OC. Epub 2006 Oct 12.
IL-18 is known to induce IFN-gamma production, which is enhanced when combined with IL-2. In the present study, we investigated whether the combination of exogenous IL-2 and IL-18 alters airway hyperresponsiveness (AHR) and airway inflammation. Sensitized mice exposed to ovalbumin (OVA) challenge developed AHR, inflammatory cells in the bronchoalveolar lavage (BAL) fluid, and increases in levels of Th2 cytokines and goblet cell numbers. The combination of IL-2 and IL-18, but neither alone, prevented these changes while increasing levels of IL-12 and IFN-gamma. The combination of IL-2 and IL-18 was ineffective in IFN-gamma-deficient and signal transducer and activator of transcription (STAT)4-deficient mice. Flow cytometry analysis showed significant increases in numbers of IFN-gamma-positive natural killer (NK) cells in the lung after treatment with the combination therapy, and transfer of lung NK cells isolated from sensitized and challenged mice treated with the combination significantly suppressed AHR and BAL eosinophilia. These data demonstrate that the combination of IL-2 and IL-18 prevents AHR and airway inflammation, likely through IL-12-mediated induction of IFN-gamma production in NK cells.
已知白细胞介素18（IL-18）可诱导γ干扰素（IFN-γ）生成，与白细胞介素2（IL-2）联合使用时，这种诱导作用会增强。在本研究中，我们调查了外源性IL-2和IL-18联合使用是否会改变气道高反应性（AHR）和气道炎症。暴露于卵清蛋白（OVA）激发的致敏小鼠出现了AHR、支气管肺泡灌洗（BAL）液中的炎性细胞，以及Th2细胞因子水平升高和杯状细胞数量增加。IL-2和IL-18联合使用可预防这些变化，单独使用则无效，同时可提高IL-12和IFN-γ水平。IL-2和IL-18联合使用对IFN-γ缺陷小鼠和信号转导及转录激活因子（STAT）4缺陷小鼠无效。流式细胞术分析显示，联合治疗后肺中IFN-γ阳性自然杀伤（NK）细胞数量显著增加，从接受联合治疗的致敏和激发小鼠中分离出的肺NK细胞转移可显著抑制AHR和BAL嗜酸性粒细胞增多。这些数据表明，IL-2和IL-18联合使用可预防AHR和气道炎症，可能是通过IL-12介导的NK细胞中IFN-γ生成诱导实现的。
