Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
Mucosal Immunol. 2010 May;3(3):301-11. doi: 10.1038/mi.2010.9. Epub 2010 Mar 17.
Interleukin (IL)-12 has been shown to suppress T helper type 2 (Th2)-induced pathogenesis that is associated with allergic asthma, largely through interferon (IFN)-gamma production. We have recently shown that in the absence of T-bet, the major regulator of IFN-gamma expression, allergic lung inflammation is primarily associated with IL-17-associated recruitment of neutrophils into the pulmonary tract of mice. In the absence of T-bet, exogenous IL-12 was still able to suppress neutrophilic infiltration and to diminish levels of IL-17, IL-23, and IL-23R, as well as retinoic acid-related orphan receptor gamma t, the transcriptional regulator of the Th17 pathway. The same effects were observed in T-bet(-/-) IFN-gamma(-/-) double knockout mice, showing an IFN-gamma-independent effect of IL-12 in this model. IL-10 expression in the lungs of T-bet-deficient mice was significantly increased after IL-12 treatment, and inoculation of anti-IL-10R mAb completely reversed the ability of IL-12 to suppress histological inflammation, recruitment of inflammatory cell subsets into the lung, bronchiole hyperresponsiveness, and IL-17 production. We conclude that Th17-mediated allergic lung inflammation that becomes dominant in the absence of effective IFN-gamma signaling can be effectively suppressed by IL-12 through an IL-10-dependent mechanism.
白细胞介素（IL）-12 已被证明可抑制与过敏性哮喘相关的 T 辅助型 2（Th2）诱导的发病机制，主要通过干扰素（IFN）-γ产生。我们最近表明，在缺乏 T 细胞特异性转录因子（T-bet）的情况下，IFN-γ表达的主要调节因子，过敏性肺炎症主要与 IL-17 相关的中性粒细胞募集到小鼠的肺部途径有关。在缺乏 T-bet 的情况下，外源性 IL-12 仍能够抑制中性粒细胞浸润，并降低 IL-17、IL-23 和 IL-23R 以及维甲酸相关孤儿受体γ t（Th17 途径的转录调节剂）的水平。在 T-bet（-/-）IFN-γ（-/-）双重基因敲除小鼠中观察到相同的效果，表明在该模型中 IL-12 具有 IFN-γ 非依赖性作用。在缺乏 T-bet 的小鼠肺中，IL-12 治疗后 IL-10 的表达显著增加，并且接种抗 IL-10R mAb 完全逆转了 IL-12 抑制组织炎症、炎症细胞亚群向肺内募集、细支气管高反应性和 IL-17 产生的能力。我们得出结论，在缺乏有效 IFN-γ 信号的情况下，Th17 介导的过敏性肺炎症变得占主导地位，可以通过 IL-10 依赖的机制被 IL-12 有效抑制。
