Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis.
Augmentation of Valpha14 NKT cell-mediated cytotoxicity by interleukin 4 in an autocrine mechanism resulting in the development of concanavalin A-induced hepatitis.
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DOI：
10.1084/jem.191.1.105
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发表时间：
2000-01-03
影响因子：
15.3
通讯作者：
Taniguchi, M
中科院分区：
文献类型：
--
作者：
Kaneko, Y;Harada, M;Kawano, T;Yamashita, M;Shibata, Y;Gejyo, F;Nakayama, T;Taniguchi, M
伴刀豆球蛋白A（ConA）的给药诱导小鼠肝细胞的快速严重损伤。虽然Con A诱导的肝炎被认为是人类自身免疫性肝炎的实验模型，但诱导肝细胞损伤的确切细胞和分子机制仍不清楚。在这里，我们证明Vα14 NKT细胞是诱导这种肝炎所必需的，也是足够的。此外，发现由Con A激活的Vα14 NKT细胞产生的白细胞介素（IL）-4通过以自分泌方式增强Vα14 NKT细胞的细胞毒活性在疾病发展中起关键作用。事实上，IL-4短期处理诱导Vα14 NKT细胞中颗粒酶B和Fas配体（L）表达增加。此外，来自穿孔素敲除小鼠或FasL突变型gld/gld小鼠的Vα14 NKT细胞不能诱导肝炎，因此穿孔素颗粒酶B和FasL似乎是Con A诱导的Vα14 NKT细胞介导的肝细胞损伤的效应分子。
The administration of concanavalin A (Con A) induces a rapid severe injury of hepatocytes in mice. Although the Con A–induced hepatitis is considered to be an experimental model of human autoimmune hepatitis, the precise cellular and molecular mechanisms that induce hepatocyte injury remain unclear. Here, we demonstrate that Vα14 NKT cells are required and sufficient for induction of this hepatitis. Moreover, interleukin (IL)-4 produced by Con A–activated Vα14 NKT cells is found to play a crucial role in disease development by augmenting the cytotoxic activity of Vα14 NKT cells in an autocrine fashion. Indeed, short-term treatment with IL-4 induces an increase in the expression of granzyme B and Fas ligand (L) in Vα14 NKT cells. Moreover, Vα14 NKT cells from either perforin knock-out mice or FasL-mutant gld/gld mice fail to induce hepatitis, and hence perforin–granzyme B and FasL appear to be effector molecules in Con A–induced Vα14 NKT cell–mediated hepatocyte injury.