Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist
Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist
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DOI：
10.1038/labinvest.2008.110
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发表时间：
2009-01-01
影响因子：
5
通讯作者：
Kondo, Toshikazu
中科院分区：
文献类型：
--
作者：
Ishibe, Takuya;Kimura, Akihiko;Kondo, Toshikazu
腹膜内给药时，对乙酰氨基酚 (APAP) 会诱导肝内白细胞介素 (IL)-1 α、IL-1 β 和 IL-1 受体拮抗剂 (IL-1ra) 表达增加。这些观察结果促使我们确定 IL-1ra 在 APAP 诱导的肝损伤中的病理生理学作用。与野生型（WT）小鼠来源的肝细胞相比，IL-1ra缺陷（IL-1ra KO）来源的肝细胞对APAP表现出更强的抵抗力，但对APAP来源的主要毒性代谢物N-乙酰基对苯醌亚胺（NAPQI）没有表现出更强的抵抗力。此外，IL-1ra KO 小鼠中主要 APAP 加合物（硒结合蛋白）的含量（APAP 生成 NAPQI 的指标）显着低于 CYP1A2、CYP2E1 和 CYP3A11（这些酶在 APAP 生成 NAPQI 中至关重要的酶）肝内表达降低的 WT 小鼠中显着降低。这些观察结果表明 IL-1ra 缺乏会损害 APAP 代谢。 IL-1α和IL-1β在未治疗的IL-1ra KO和WT小鼠的肝脏中表达程度相似。相比之下，未经处理的 IL-1ra KO 小鼠的核内 NF-kB p65 量（可抑制 CYP1A2、CYP2E1 和 CYP3A11 的基因表达）高于 WT 小鼠。此外，当小鼠腹腔注射 APAP（200 mg/kg）时，IL-1ra KO 小鼠表现出 APAP 诱导的肝损伤减轻，血清丙氨酸转移酶水平降低以及小叶中心坏死、出血和白细胞浸润等组织病理学变化证明了这一点。最后，在 APAP 攻击前 12 小时给予 IL-1 α 抑制 CYP1A2、CYP2E1 和 CYP3A11 的肝内表达，最终减少 APAP 诱导的肝损伤，同时减少 APAP 加合物。总的来说，NF-kB 在没有任何刺激的情况下通过 IL-1ra 的基因破坏而被激活，并抑制细胞色素 P450 酶的表达，从而减少 APAP 诱导的肝损伤。
Acetaminophen ( APAP) induced increases in intrahepatic expression of interleukin (IL)-1 alpha, IL-1 beta, and IL-1 receptor antagonist (IL-1ra), when administered intraperitoneally. These observations prompted us to define the pathophysiological roles of IL-1ra in APAP-induced liver injury. Compared with wild-type (WT) mouse-derived hepatocytes, IL-1ra-deficient (IL-1ra KO)-derived hepatocytes exhibited more resistance against APAP but not APAP-derived major toxic metabolite, N-acetyl-p-benzoquinone imine ( NAPQI). Moreover, the amounts of a major APAP adduct (selenium-binding protein), an indicator of NAPQI generation from APAP, was significantly lower in IL-1ra KO mice than WT mice with depressed intrahepatic expression of CYP1A2, CYP2E1, and CYP3A11, the enzymes crucially involved in NAPQI generation from APAP. These observations would indicate that IL-1ra deficiency impaired APAP metabolism. IL-1 alpha and IL-1 beta were expressed to similar extents in livers of untreated IL-1ra KO and WT mice. By contrast, the intranuclear amount of p65 of NF-kB, which can suppress the gene expression of CYP1A2, CYP2E1, and CYP3A11, was higher in untreated IL-1ra KO than WT mice. Moreover, when mice were intraperitoneally administered APAP ( 200 mg/kg), IL-1ra KO mice exhibited attenuated APAP-induced liver injury as evidenced by reductions in serum alanine transferase levels and histopathological changes such as centrilobular necrosis, hemorrhages, and leukocyte infiltration. Finally, when given 12 h before APAP challenge, IL-1 alpha repressed the intrahepatic expression of CYP1A2, CYP2E1, and CYP3A11, eventually reducing APAP-induced liver injury, along with reduction in APAP adducts. Collectively, NF-kB was activated without any stimuli by the genetic disruption of IL-1ra, and suppressed cytochrome P450 enzyme expression, thereby reducing APAP-induced liver injury.