Department of Immunoregulation, Institute of Medical Science, Tokyo Medical University, Shinjuku-ku, Tokyo, Japan.
Eur J Immunol. 2011 Oct;41(10):2828-39. doi: 10.1002/eji.201141291. Epub 2011 Aug 31.
IL-23 plays a critical role in the expansion of highly proinflammatory Th17 cells secreting IL-17 and IL-22. Recently, we demonstrated that Notch signaling drives IL-22 secretion through the aryl hydrocarbon receptor (AHR) and plays a protective role in Con A-induced hepatitis. In this study, we investigated the role of IL-23 in hepatitis using IL-23p19- and IL-17-deficient mice. In WT mice, the injection of Con A induced the upregulation of various cytokines, which included IL-23, IL-22, IL-17, IFN-γ and TNF-α. In IL-23p19-deficient mice, exacerbated hepatitis was observed and serum IL-22 and IL-17 levels were greatly reduced, whereas in IL-17-deficient mice, ameliorated hepatitis was observed. The injection of exogenous IL-22 protected p19-deficient mice from hepatitis, whereas the injection of exogenous IL-23 significantly increased the serum levels of not only IL-22 but also IL-17, and less effectively protected against hepatitis in IL-17-dependent and -independent manners. Finally, it was revealed that STAT3, STAT4 and Notch contributed to the production of both the cytokines, and that the AHR was important only for IL-22 production in response to Con A and IL-23 in liver mononuclear cells. These results suggest that IL-23 plays a protective role in hepatitis through IL-22 production and also a pathological role via IL-17-dependent and -independent mechanisms.
IL-23 在高度促炎 Th17 细胞的扩增中发挥关键作用，这些细胞分泌 IL-17 和 IL-22。最近，我们证明 Notch 信号通过芳香烃受体 (AHR) 驱动 IL-22 的分泌，并在 Con A 诱导的肝炎中发挥保护作用。在这项研究中，我们使用 IL-23p19 缺陷型和 IL-17 缺陷型小鼠研究了 IL-23 在肝炎中的作用。在 WT 小鼠中，Con A 的注射诱导了各种细胞因子的上调，包括 IL-23、IL-22、IL-17、IFN-γ 和 TNF-α。在 IL-23p19 缺陷型小鼠中，观察到肝炎加重，血清 IL-22 和 IL-17 水平大大降低，而在 IL-17 缺陷型小鼠中，观察到肝炎减轻。外源性 IL-22 的注射可保护 p19 缺陷型小鼠免受肝炎，而外源性 IL-23 的注射不仅显著增加了血清中 IL-22 的水平，而且以 IL-17 依赖和非依赖的方式更有效地保护免受肝炎。最后，揭示了 STAT3、STAT4 和 Notch 有助于这两种细胞因子的产生，并且 AHR 对于 Con A 和肝单核细胞中 IL-23 对 IL-22 产生的反应是重要的。这些结果表明，IL-23 通过 IL-22 的产生在肝炎中发挥保护作用，并且通过 IL-17 依赖和非依赖机制发挥病理性作用。
