Wakashin Hidefumi, Hirose Koichi, Maezawa Yuko, Kagami Shin-ichiro, Suto Akira, Watanabe Norihiko, Saito Yasushi, Hatano Masahiko, Tokuhisa Takeshi, Iwakura Yoichiro, Puccetti Paolo, Iwamoto Itsuo, Nakajima Hiroshi
Department of Allergy and Clinical Immunology, Chiba University Hospital, Chiba, Japan.
Am J Respir Crit Care Med. 2008 Nov 15;178(10):1023-32. doi: 10.1164/rccm.200801-086OC. Epub 2008 Sep 11.
The IL-23-IL-17A-producing CD4(+) T-cell (Th17 cell) axis plays an important role in the development of chronic inflammatory diseases, including autoimmune diseases. However, the role of the IL-23-Th17 cell axis in the regulation of allergic airway inflammation is still largely unknown.
To determine the role of IL-23 and Th17 cells in allergic airway inflammation.
We examined the effect of anti-IL-23 antibody on antigen-induced airway inflammation. We also investigated the effect of enforced expression of IL-23 on allergic airway inflammation by generating lung-specific IL-23 transgenic mice. Moreover, we examined the effect of adoptive transfer of antigen-specific Th17 cells on allergic airway inflammation.
IL-23 mRNA was expressed in the lung of sensitized mice upon antigen inhalation, and the neutralization of IL-23 decreased antigen-induced eosinophil recruitment and Th2 cytokine production in the airways. The enforced expression of IL-23 in the airways significantly enhanced antigen-induced eosinophil and neutrophil recruitment into the airways; Th2 cytokine, IL-17A, and tumor necrosis factor (TNF)-alpha production in the airways; goblet cell hyperplasia; and airway hyperresponsiveness. Moreover, IL-23-mediated enhancement of antigen-induced Th2 cytokine production and eosinophil recruitment in the airways was still observed in the mice lacking IL-17A. Furthermore, although adoptive transfer of antigen-specific Th17 cells alone induced neutrophil but not eosinophil recruitment into the airways upon antigen inhalation, cotransfer of Th17 cells with Th2 cells significantly enhanced antigen-induced Th2-cell-mediated eosinophil recruitment into the airways and airway hyperresponsiveness.
IL-23 and Th17 cells not only induce Th17-cell-mediated neutrophilic airway inflammation but also up-regulate Th2-cell-mediated eosinophilic airway inflammation.
产生白细胞介素-23（IL-23）和白细胞介素-17A（IL-17A）的CD4(+) T细胞（Th17细胞）轴在包括自身免疫性疾病在内的慢性炎症性疾病的发展中起重要作用。然而，IL-23-Th17细胞轴在过敏性气道炎症调节中的作用仍在很大程度上未知。
确定IL-23和Th17细胞在过敏性气道炎症中的作用。
我们检测了抗IL-23抗体对抗原诱导的气道炎症的影响。我们还通过生成肺特异性IL-23转基因小鼠来研究IL-23的强制表达对过敏性气道炎症的影响。此外，我们检测了过继转移抗原特异性Th17细胞对过敏性气道炎症的影响。
致敏小鼠在吸入抗原后肺中表达IL-23 mRNA，中和IL-23可减少抗原诱导的气道嗜酸性粒细胞募集和Th2细胞因子产生。气道中IL-23的强制表达显著增强了抗原诱导的嗜酸性粒细胞和中性粒细胞向气道的募集；气道中Th2细胞因子、IL-17A和肿瘤坏死因子（TNF）-α的产生；杯状细胞增生；以及气道高反应性。此外，在缺乏IL-17A的小鼠中仍观察到IL-23介导的抗原诱导的气道Th2细胞因子产生和嗜酸性粒细胞募集增强。此外，虽然单独过继转移抗原特异性Th17细胞在吸入抗原后可诱导中性粒细胞而非嗜酸性粒细胞向气道募集，但Th17细胞与Th2细胞共转移可显著增强抗原诱导的Th2细胞介导的嗜酸性粒细胞向气道的募集和气道高反应性。
IL-23和Th17细胞不仅诱导Th17细胞介导的嗜中性气道炎症，还上调Th2细胞介导的嗜酸性气道炎症。
