Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely susceptible to acetaminophen-induced liver injury
Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely susceptible to acetaminophen-induced liver injury
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DOI：
10.1021/tx060228l
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发表时间：
2007-02-01
影响因子：
4.1
通讯作者：
Pohl, Lance R.
中科院分区：
文献类型：
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作者：
Bourdi, Mohammed;Eiras, Daniel P.;Pohl, Lance R.
由于缺乏动物模型，药物性肝炎对药物开发和安全性仍然是一个具有挑战性的问题。在目前的工作中，我们发现了一种独特的相互作用，使同时缺乏IL-10和IL-4(IL-10/4(-/-))的小鼠对对乙酰氨基酚(APAP)的肝脏毒性作用高度敏感。用120 mg/kg APAP处理雄性C57BL/6野生型(WT)和一种或多种细胞因子缺陷小鼠。在WT后24小时内，IL-10(-/-)、IL-4(-/-)或IL-10/4(-/-)小鼠接受APAP治疗后，75%的IL-10/4(-/-)小鼠死于大量肝损伤，而所有其他基因型的小鼠均对该剂量的APAP的肝毒性耐受。IL-10/4(-/-)小鼠独特的易感性与肝脏谷胱甘肽水平降低和血清IL-6水平显著升高以及几种致炎因子有关，包括肿瘤坏死因子-α、干扰素-γ、巨噬细胞炎性蛋白-1α(MIP-1α)、单核细胞趋化蛋白-1(MCP-1)、巨噬细胞炎性蛋白-2(MIP-2)、骨桥蛋白(OPN)和一氧化氮(NO)。IL-6中和抗体逆转了IL-10/4(-/-)小鼠对APAP诱导的肝病(AILD)的高度敏感性，因此IL-6似乎在控制这些小鼠对APAP诱导的肝病(AILD)的独特易感性方面具有因果作用。此外，IL-10/4/6(-/-)小鼠对增强的AILD易感性也具有抵抗力，并且大多数促炎因子基因的表达水平相对较低，而IL-10/4(-/-)小鼠的表达水平较高。总之，AILD后的肝脏动态平衡似乎高度依赖于IL-10和IL-4的活性，这两种活性共同有助于防止IL-6和其他潜在的肝毒性因子的过度表达。
Drug-induced hepatitis remains a challenging problem for drug development and safety because of the lack of animal models. In the current work, we discovered a unique interaction that makes mice deficient in both IL-10 and IL-4 (IL-10/4(-/-)) highly sensitive to the hepatotoxic effects of acetaminophen (APAP). Male C57Bl/6 wild type (WT) and mice deficient in one or more cytokines were treated with 120 mg/kg APAP. Within 24 h after WT, IL-10(-/-), IL-4(-/-), or IL-10/4(-/-) mice were administered APAP, 75% of the IL-10/4(-/-) mice died of massive hepatic injury while all other genotypes were resistant to liver toxicity at this dose of APAP. The unique susceptibility of IL-10/4(-/-) mice was associated with reduced levels of liver glutathione and remarkably high serum levels of IL-6 and several proinflammatory factors including TNF-alpha, IFN-gamma, macrophage inflammatory protein-1 alpha (MIP-1 alpha), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and osteopontin (OPN) as well as nitric oxide (NO). IL-6 appeared to have a causal role in controlling the unique susceptibility of IL-10/4(-/-) mice to APAP-induced liver disease (AILD) because IL-6 neutralizing antibody reversed the high sensitivity of these mice to AILD. Moreover, IL-10/4/6(-/-) mice were also resistant to the enhanced susceptibility to AILD and expressed relatively low levels of most proinflammatory factor genes that were elevated in the IL-10/4(-/-) mice. In conclusion, liver homeostasis following AILD appears to be highly dependent on the activities of both IL-10 and IL-4, which together help prevent overexpression of IL-6 and other potential hepatotoxic factors.