Superoxide Produced by Kupffer Cells Is an Essential Effector in Concanavalin A-induced Hepatitis in Mice
Superoxide Produced by Kupffer Cells Is an Essential Effector in Concanavalin A-induced Hepatitis in Mice
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DOI：
10.1002/hep.22561
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发表时间：
2008-12-01
期刊：
影响因子：
13.5
通讯作者：
Seki, Shuhji
中科院分区：
文献类型：
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作者：
Nakashima, Hiroyuki;Kinoshita, Manabu;Seki, Shuhji
虽然刀豆球蛋白A（Con-A）诱导的实验性肝炎被认为是由活化的T细胞，自然杀伤T（NKT）细胞和细胞因子诱导的，但确切的机制仍然未知。在本研究中，我们研究了库普弗细胞，NKT细胞，FasL，肿瘤坏死因子（TNF）和超氧化物在C57 BL/6小鼠Con-A肝炎中的作用。使用氯化钆（GdCl 3）从肝脏中去除枯否细胞完全抑制了Con-A肝炎，而血清TNF和IFN-γ水平的升高根本没有受到抑制。出乎意料的是，抗FasL抗体预处理不抑制Con-A肝炎，而它抑制由NKT细胞的合成配体α-半乳糖神经酰胺诱导的肝损伤。此外，GdCl 3预处理既不改变活化诱导的NK1.1抗原和NKT细胞的T细胞受体的下调，也不改变肝T细胞的CD 69活化抗原的表达增加。在Con-A注射后的早期阶段，CD 68（+）Kupffer细胞的比例大大增加;这种增加被GdCl 3预处理所消除。抗TNF抗体（Ab）预处理不能抑制枯否细胞的增加，但能有效抑制枯否细胞产生超氧化物/活性氧，并抑制由此引起的肝损伤。相反，通过NK1.1 Ab预处理去除小鼠中的NKT细胞确实抑制了CD 68（+）Kupffer细胞的增加和Con-A肝炎。因此，通过使用自由基清除剂减少枯否细胞产生的氧自由基可以极大地抑制Con-A肝炎，而不抑制细胞因子的产生。然而，过继转移实验也表明库普弗细胞与NKT细胞的密切相互作用/合作对于Con-A肝炎至关重要。结论：库普弗细胞产生的超氧化物可能是Con-A肝炎中的重要效应子，TNF和NKT细胞支持其活化和超氧化物的产生。（《肝脏病学》2008;48：1979-1988）
Although concanavalin A (Con-A)-induced experimental hepatitis is thought to be induced by activated T cells, natural killer T (NKT) cells, and cytokines, precise mechanisms are still unknown. In the current study, we investigated the roles of Kupffer cells, NKT cells, FasL, tumor necrosis factor (TNF), and superoxide in Con-A hepatitis in C57BL/6 mice. Removal of Kupffer cells using gadolinium chloride (GdCl3) from the liver completely inhibited Con-A hepatitis, whereas increased serum TNF and IFN-gamma levels were not inhibited at all. Unexpectedly, anti-FasL antibody pretreatment did not inhibit Con-A hepatitis, whereas it inhibited hepatic injury induced by a synthetic ligand of NKT cells, a-galactosylceramide. Furthermore, GdCl3 pretreatment changed neither the activation-induced down-regulation of NK1.1 antigens as well as T cell receptors of NKT cells nor the increased expression of the CD69 activation antigen of hepatic T cells. CD68(+) Kupffer cells greatly increased in proportion in the early phase after Con-A injection; this increase was abrogated by GdCl3 pretreatment. Anti-TNF antibody (Ab) pretreatment did not inhibit the increase of Kupffer cells, but it effectively suppressed superoxide/reactive oxygen production from Kupffer cells and the resulting hepatic injury. Conversely, depletion of NKT cells in mice by NK1.1 Ab pretreatment did suppress both the increase of CD68(+) Kupffer cells and Con-A hepatitis. Consistently, the diminution of oxygen radicals produced by Kupffer cells by use of free radical scavengers greatly inhibited Con-A hepatitis without suppressing cytokine production. However, adoptive transfer experiments also indicate that a close interaction/cooperation of Kupffer cells with NKT cells is essential for Con-A hepatitis. Conclusion: Superoxide produced by Kupffer cells may be the essential effector in Con-A hepatitis, and TNF and NKT cells support their activation and superoxide production. (HEPATOLOGY 2008;48:1979-1988.)