Highly liver-specific heme oxygenase-1 induction by interleukin-11 prevents carbon tetrachloride-induced hepatotoxicity.
Highly liver-specific heme oxygenase-1 induction by interleukin-11 prevents carbon tetrachloride-induced hepatotoxicity.
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DOI：
10.3892/ijmm.18.4.537
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发表时间：
2006-10
影响因子：
5.4
通讯作者：
T. Kawakami;Toru Takahashi;H. Shimizu;K. Nakahira;M. Takeuchi;H. Katayama;M. Yokoyama;K. Morita;R. Akagi;S. Sassa
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文献类型：
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作者：
T. Kawakami;Toru Takahashi;H. Shimizu;K. Nakahira;M. Takeuchi;H. Katayama;M. Yokoyama;K. Morita;R. Akagi;S. Sassa
血红素加氧酶（HO）-1是血红素催化剂的限速酶，在各种氧化刺激下可被诱导，它的诱导在细胞防御氧化性组织损伤中起关键作用。四氯化碳（CCl（4））处理大鼠会导致细胞膜脂质过氧化，并产生严重的肝损伤。我们以前证明，HO-1诱导后，CCl（4）处理是一个重要的一部分，细胞防御的CCl（4）诱导的毒性变化。由于重组人白细胞介素-11（rhIL-11）可诱导培养的肝癌细胞产生HO-1，我们在大鼠体内研究了rhIL-11对四氯化碳诱导的组织损伤的影响。rhIL-11单独处理动物显著诱导HO-1 mRNA及其功能蛋白主要在肝脏中。rhIL-11处理（150 μ g/kg）CCl（4）给药（1 ml/kg）动物导致HO-1 mRNA进一步增加，同时显著抑制CCl（4）诱导的血清丙氨酸转氨酶、肝丙二醛形成、肿瘤坏死因子-α mRNA、一氧化氮合酶mRNA、核因子-κ B DNA结合活性以及肝细胞的炎症变化。相比之下，HO竞争性特异性抑制剂锡-中卟啉对HO活性的抑制完全消除了rhIL-11的细胞保护作用。这些结果表明，rhIL-11通过其肝脏特异性HO-1诱导，对CCl（4）诱导的肝损伤具有显著的保护作用。
Heme oxygenase (HO)-1, the rate-limiting enzyme in heme catabolism, can be induced in response to various oxidative stimuli, and its induction is thought to be critical in the cellular defense against oxidative tissue injuries. Carbon tetrachloride (CCl(4)) treatment of rats causes lipid peroxidation of cell membranes and produces massive hepatic injury. We previously demonstrated that HO-1 induction following CCl(4) treatment is an essential part of the cellular defense against the CCl(4)-inducible toxic changes. As recombinant human interleukin-11 (rhIL-11) has been shown to induce HO-1 in cultured hepatoma cells, we examined the effect of rhIL-11 in vivo in rats on the CCl(4)-induced tissue injury. rhIL-11 treatment of animals by itself markedly induced HO-1 mRNA and its functional protein principally in the liver. rhIL-11 treatment (150 microg/kg) of the CCl(4)-administered (1 ml/kg) animals led to a further increase in HO-1 mRNA, while it markedly suppressed CCl(4)-induced serum alanine transaminase, hepatic malondialdehyde formation, tumor necrosis factor-alpha mRNA, nitric oxide synthase mRNA, nuclear factor-kappaB DNA-binding activity, as well as inflammatory changes of hepatocytes. In contrast, inhibition of HO activity by tin-mesoporphyrin, a competitive specific inhibitor of HO, entirely abolished the cytoprotective effect of rhIL-11. These findings thus demonstrate that rhIL-11 confers significant protection against CCl(4)-induced hepatic injury by virtue of its liver-specific HO-1 induction.