Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity
Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity
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DOI：
10.1053/j.gastro.2004.08.053
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发表时间：
2004-12-01
期刊：
影响因子：
29.4
通讯作者：
Kaplowitz, N
中科院分区：
文献类型：
--
作者：
Liu, ZX;Govindarajan, S;Kaplowitz, N
背景与目的：肝脏非实质炎性细胞释放的炎性介质与对乙酰氨基酚（APAP）肝毒性的进展有关。在肝脏非实质炎性细胞中，我们研究了丰富的自然杀伤（NK）细胞以及具有T细胞受体的NK细胞（NKT细胞）在APAP诱导的肝损伤中的作用。
方法：向C57BL/6小鼠腹腔内给予有毒剂量的APAP以造成肝损伤，同时使用或不使用抗NK1.1单克隆抗体（MAb）耗竭NK和NKT细胞。评估血清丙氨酸转氨酶（ALT）水平、肝脏组织学、肝脏白细胞聚集以及细胞因子/趋化因子表达。
结果：与APAP处理的对照小鼠相比，通过抗NK1.1耗竭NK和NKT细胞显著保护小鼠免受APAP诱导的肝损伤，这表现为血清ALT水平降低、小鼠存活率提高、肝脏坏死减少、干扰素 - γ（IFN - γ）、Fas配体（FasL）以及包括KC（角质细胞衍生趋化因子）、MIP - 1α（巨噬细胞炎性蛋白 - 1α）、MCP - 1（单核细胞趋化蛋白 - 1）、IP - 10（干扰素诱导蛋白）、Mig（IFN - γ诱导的单核因子）在内的趋化因子的信使RNA（mRNA）表达受到抑制，以及肝脏中中性粒细胞聚集减少。通过细胞内细胞因子染色确定肝脏NK和NKT细胞是IFN - γ的主要来源。与野生型小鼠相比，APAP在Fas缺陷（Ipr）和FasL缺陷（gld）小鼠中诱导的肝损伤要少得多。
结论：NK和NKT细胞通过分泌IFN - γ、调节趋化因子产生和中性粒细胞聚集以及上调肝脏中FasL的表达，在APAP诱导的肝损伤进展中起关键作用，所有这些都可能促进肝脏固有免疫系统的炎症反应，从而导致APAP代谢以及肝细胞中还原型谷胱甘肽（GSH）耗竭下游的肝损伤的严重程度和进展。
Background & Aims: Inflammatory mediators released by nonparenchymal inflammatory cells in the liver have been implicated in the progression of acetaminophen (APAP) hepatotoxicity. Among hepatic nonparenchymal inflammatory cells, we examined the role of the abundant natural killer (NK) cells and NK cells with T-cell receptors (NKT cells) in APAP-induced liver injury. Methods: C57BL/6 mice were administered a toxic dose of APAP intraperitoneally to cause liver injury with or without depletion of NK and NKT cells by anti-NK1.1 monoclonal antibody (MAb). Serum alanine transaminase (ALT) levels, liver histology, hepatic leukocyte accumulation, and cytokine/chemokine expression were assessed. Results: Compared with APAP-treated control mice, depletion of both NK and NKT cells by anti-NK1.1 significantly protected mice from APAP-induced liver injury, as evidenced by decreased serum ALT level, improved survival of mice, decreased hepatic necrosis, inhibition of messenger RNA (mRNA) expression for interferon-gamma (IFN-gamma), Fas ligand (FasL), and chemokines including KC (Keratinocyte-derived chemokine); MIP-1alpha (macrophage inflammatory protein-1alpha); MCP-1 (monocyte chemoattractant protein-1); IP-10 (interferon-inducible protein); Mig (monokine induced by IFN-gamma) and decreased neutrophil accumulation in the liver. Hepatic NK and NKT cells were identified as the major source of IFN-gamma by intracellular cytokine staining. APAP induced much less liver injury in Fas-deficient (Ipr) and FasL-deficient (gld) mice compared with that, in wild-type mice. Conclusions: NK and NKT cells play a critical role in the progression of APAP-induced liver injury by secreting IFN-gamma, modulating chemokine production and accumulation of neutrophils, and up-regulating FasL expression in the liver, all of which may promote the inflammatory response of liver innate immune system, thus contributing to the severity and progression of liver injury downstream of the metabolism of APAP and depletion of reduced glutathione (GSH) in hepatocytes.