Fujita Hiroyuki, Teng Annabelle, Nozawa Risa, Takamoto-Matsui Yukiko, Katagiri-Matsumura Haruka, Ikezawa Zenro, Ishii Yasuyuki
RIKEN Research Center for Allergy and Immunology, Suehiro, Tsurumi, Yokohama, Kanagawa, Japan.
J Immunol. 2009 Jul 1;183(1):254-60. doi: 10.4049/jimmunol.0800520.
Using an allergen-induced airway inflammation model, we show that an injection of alpha-galactosylceramide (alpha-GalCer), a ligand for invariant NK T (iNKT) cells, induced IL-27 and that this process is essential for the attenuation of the Th2 response. After the systemic administration of alpha-GalCer into the mice primed with OVA in alum, Th2 cytokine production of OVA-primed CD4(+) T cells in their lymph nodes, IgG1 and IgE Ab formation, and infiltration of eosinophils in bronchoalveolar lavage after the OVA challenge were suppressed. Systemic administration of rIFN-gamma into OVA-primed mice could not reproduce these effects of alpha-GalCer. IL-27p28 was detected both in the culture supernatant of alpha-GalCer-stimulated spleen cells and in the serum of the alpha-GalCer-treated mice, but not in the iNKT cell-deficient mice. Splenic iNKT cells produced IL-27p28 in the culture supernatant upon stimulation with PMA plus ionomycin, although the transcript of IL-27p28 in the iNKT cells was constitutively expressed regardless of the stimulation. By contrast, the transcript of IL-27EBI3 was induced in the iNKT cells upon stimulation with PMA plus ionomycin in vitro and with alpha-GalCer treatment in vivo, suggesting that IL-27 (p28/EBI3) could be produced by iNKT cells in an activation-dependent manner. Although repeated injections of rIL-27 did not substitute for the effects of a single injection of alpha-GalCer, administration of rIL-27 along with rIFN-gamma reproduced in vivo effects of the alpha-GalCer injection. These data indicate that production of both IL-27 and IFN-gamma by the alpha-GalCer treatment is responsible for suppression of the Th2 response and allergic inflammation.
利用变应原诱导的气道炎症模型，我们发现注射α-半乳糖神经酰胺（α-GalCer），一种恒定自然杀伤T（iNKT）细胞的配体，可诱导白细胞介素-27（IL-27）产生，且这一过程对于减轻Th2反应至关重要。在对用明矾中的卵清蛋白（OVA）致敏的小鼠进行α-GalCer全身给药后，OVA致敏的CD4(+) T细胞在其淋巴结中的Th2细胞因子产生、IgG1和IgE抗体形成以及OVA激发后支气管肺泡灌洗中嗜酸性粒细胞的浸润均受到抑制。对OVA致敏的小鼠全身给予重组干扰素-γ（rIFN-γ）无法重现α-GalCer的这些作用。在α-GalCer刺激的脾细胞培养上清液以及α-GalCer处理的小鼠血清中均检测到IL-27p28，但在iNKT细胞缺陷小鼠中未检测到。脾iNKT细胞在佛波酯（PMA）加离子霉素刺激后在培养上清液中产生IL-27p28，尽管iNKT细胞中IL-27p28的转录本无论是否受到刺激均组成性表达。相比之下，IL-27EBI3的转录本在体外PMA加离子霉素刺激以及体内α-GalCer处理后在iNKT细胞中被诱导，这表明IL-27（p28/EBI3）可能由iNKT细胞以激活依赖的方式产生。尽管重复注射重组白细胞介素-27（rIL-27）不能替代单次注射α-GalCer的作用，但rIL-27与rIFN-γ联合给药可重现α-GalCer注射的体内作用。这些数据表明，α-GalCer处理导致的IL-27和干扰素-γ产生均负责抑制Th2反应和过敏性炎症。
