Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair
Paradoxical effects of short- and long-term interleukin-6 exposure on liver injury and repair
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DOI：
10.1002/hep.21087
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发表时间：
2006-03-01
期刊：
影响因子：
13.5
通讯作者：
Koniaris, LG
中科院分区：
文献类型：
--
作者：
Jin, XL;Zimmers, TA;Koniaris, LG
白细胞介素-6（IL-6）是肝脏再生和修复的重要介质，在慢性肝病（包括肥胖性脂肪肝和肝硬化）中也升高。据报道，IL-6可以延迟和加速肝再生。我们研究了通过在无胸腺裸鼠中注射表达IL-6的CHO细胞系和通过渗透性微泵递送重组鼠IL-6对小鼠连续施用外源性IL-6对肝损伤和再生的影响。短期IL-6给药（1-2天）加速肝脏质量的早期恢复，而更长期的给药（5-7天）明显损害肝再生。同样，短期IL-6治疗增加肝脏抵抗Fas激动剂Jo-2的致死作用，但更长时间的IL-6暴露的Jo-2阻力消失。IL-6给药最初诱导抗凋亡蛋白Bcl-2和BCI-X-L的表达，与针对Fas介导的细胞死亡的保护相关。然而，更长时间的IL-6给药导致促凋亡蛋白Bax的显著诱导。这一结果与11型或内在的线粒体细胞死亡途径的激活增加相一致，表现为在Jo-2暴露后半胱天冬酶-9激活增加和细胞色素c释放增加。这些数据表明，IL-6可以急性作用，以改善肝再生和修复，但更多的慢性暴露不仅取消了IL-6的保护作用，但实际上使肝脏对损伤和死亡敏感。总之，在某些慢性肝病中升高的IL-6有助于增加损伤后肝衰竭的可能性。
Interleukin-6 (IL-6) is an important mediator of liver regeneration and repair that is also elevated in chronic liver diseases, including fatty liver of obesity and cirrhosis. IL-6 has been reported both to delay and accelerate liver regeneration. We examined the effects on liver injury and regeneration of a continuous administration of exogenous IL-6 to mice by injection of an IL-6-expressing CHO-cell line in athymic nude mice and by osmotic mini-pump delivery of recombinant murine IL-6. Short-term IL-6 administration (1-2 days) accelerated early recovery of liver mass, whereas more long-term administration (5-7 days) markedly impaired liver regeneration. Similarly, short-term IL-6 treatment increased hepatic resistance to the lethal effects of the Fas agonist Jo-2, but on more prolonged IL-6 exposure the Jo-2 resistance vanished. IL-6 administration initially induced expression of the anti-apoptotic proteins Bcl-2 and BCI-X-L, correlating with protection against Fas-mediated cell death. More prolonged IL-6 administration, however, resulted in marked induction of the proapoptotic protein Bax. This result coincided with increased activation of the type 11 or intrinsic, mitochondrial path to cell death, manifested by increased caspase-9 activation and increased cytochrome c release after Jo-2 exposure. These data demonstrate that IL-6 can function acutely to improve hepatic regeneration and repair, but that more chronic exposure not only abolishes the protective effects of IL-6, but actually sensitizes the liver to injury and death. In conclusion, elevated IL-6 in certain chronic liver diseases contributes to an increased likelihood of liver failure after injury.