Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
J Immunol. 2010 Aug 15;185(4):2536-43. doi: 10.4049/jimmunol.1000092. Epub 2010 Jul 12.
NKT cells are remarkably abundant in mouse liver. Compelling experimental evidence has suggested that NKT cells are involved in the pathogenesis of many liver diseases. Activation of NKT cells with alpha-galactosylceramide (alpha-GalCer) causes liver injury through mechanisms that are not well understood. We undertook studies to characterize the key pathways involved in alpha-GalCer-induced liver injury. We found that expression of the transcription factor IFN regulatory factor 1 (IRF-1) in mouse liver was dramatically upregulated by alpha-GalCer treatment. Neutralization of either TNF-alpha or IFN-gamma inhibited alpha-GalCer-mediated IRF-1 upregulation. alpha-GalCer-induced liver injury was significantly suppressed in IRF-1 knockout mice or in wild-type C56BL/6 mice that received a microRNA specifically targeting IRF-1. In contrast, overexpression of IRF-1 greatly potentiated alpha-GalCer-induced liver injury. alpha-GalCer injection also induced a marked increase in hepatic inducible NO synthase expression in C56BL/6 mice, but not in IRF-1 knockout mice. Inducible NO synthase knockout mice exhibited significantly reduced liver injury following alpha-GalCer treatment. Finally, we demonstrated that both NKT cells and hepatocytes expressed IRF-1 in response to alpha-GalCer. However, it appeared that the hepatocyte-derived IRF-1 was mainly responsible for alpha-GalCer-induced liver injury, based on the observation that inhibition of IRF-1 by RNA interference did not affect alpha-GalCer-induced NKT cell activation. Our findings revealed a novel mechanism of NKT cell-mediated liver injury in mice, which has implications in the development of human liver diseases.
NKT 细胞在小鼠肝脏中极为丰富。令人信服的实验证据表明，NKT 细胞参与了许多肝脏疾病的发病机制。用半乳糖神经酰胺（alpha-GalCer）激活 NKT 细胞会导致肝脏损伤，但具体机制尚不清楚。我们进行了研究，以确定 alpha-GalCer 诱导的肝损伤所涉及的关键途径。我们发现，alpha-GalCer 处理后，小鼠肝脏中的转录因子 IFN 调节因子 1（IRF-1）的表达显著上调。中和 TNF-α 或 IFN-γ 抑制 alpha-GalCer 介导的 IRF-1 上调。IRF-1 敲除小鼠或接受专门针对 IRF-1 的 microRNA 的野生型 C56BL/6 小鼠中，alpha-GalCer 诱导的肝损伤显著受到抑制。相反，IRF-1 的过表达大大增强了 alpha-GalCer 诱导的肝损伤。alpha-GalCer 注射还诱导 C56BL/6 小鼠肝脏中诱导型一氧化氮合酶表达的显著增加，但在 IRF-1 敲除小鼠中则没有。诱导型一氧化氮合酶敲除小鼠在 alpha-GalCer 处理后肝脏损伤明显减少。最后，我们证明 NKT 细胞和肝细胞都能对 alpha-GalCer 作出反应而表达 IRF-1。然而，基于 RNA 干扰抑制 IRF-1 不影响 alpha-GalCer 诱导的 NKT 细胞激活的观察结果，似乎主要是肝细胞衍生的 IRF-1 导致了 alpha-GalCer 诱导的肝损伤。我们的发现揭示了一种新型的 NKT 细胞介导的小鼠肝脏损伤机制，这对人类肝脏疾病的发展具有重要意义。
