The role of serpinb9/serine protease inhibitor 6 in preventing granzyme B-dependent hepatotoxicity
The role of serpinb9/serine protease inhibitor 6 in preventing granzyme B-dependent hepatotoxicity
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DOI：
10.1002/hep.21820
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发表时间：
2007-11-01
期刊：
影响因子：
13.5
通讯作者：
Thiele, Dwain L.
中科院分区：
文献类型：
--
作者：
Stout-Delgado, Heather W.;Getachew, Yonas;Thiele, Dwain L.
病毒感染的肝细胞通过穿孔素依赖性和颗粒酶依赖性效应机制对细胞毒性淋巴细胞杀伤具有抗性。本研究旨在研究丝氨酸蛋白酶抑制剂6（SPI-6）在限制肝脏颗粒酶B依赖性细胞毒性效应机制中的作用。对C57 Bl/6 J（B6）小鼠给予SPI-6特异性小干扰RNA（siRNA）可引起短暂的丙氨酸氨基转移酶（ALT）升高，而在颗粒酶B缺陷型B6（B6.gzmb（-/-））或自然杀伤（NK）细胞缺失型B6小鼠中均未观察到。当在用重组复制缺陷型腺病毒[编码β-半乳糖苷酶的E1缺失腺病毒（AdCMV-LacZ）]感染时通过siRNA施用消除SPI-6表达时，在野生型B6中观察到更早且显著增加，并且更早的ALT升高，但在B6.gzmb（-/-）NK细胞耗尽小鼠中未观察到。当向B6小鼠给予3倍高剂量的AdCMV-LacZ时，SPI-6 siRNA的联合给药导致致死性急性肝衰竭的早期发作。值得注意的是，在SPI-6 siRNA的接受者中观察到AdCMV-LacZ的加速清除。结论：这些结果表明，在病毒感染或以下非感染性肝损伤的原因，在肝细胞中的SPI-6的调节表达保护肝细胞免受过度激烈的颗粒酶B依赖性杀伤，但也可能延迟病毒感染的肝细胞的免疫清除。
Virally infected hepatocytes are resistant to cytotoxic lymphocyte killing by perforin-dependent and granzyme-dependent effector mechanisms. The present studies were designed to examine the role of serine protease inhibitor 6 (SPI-6) in limiting granzyme B-dependent cytotoxic effector mechanisms in the liver. SPI-6-specific small interfering RNA (siRNA) administration to C57Bl/6J (B6) mice elicited transient alanine aminotransferase (ALT) elevations that were not observed in either granzyme B-deficient B6 (B6.gzmb(-/-)) or natural killer (NK) cell-depleted B6 mice. When SPI-6 expression was abolished by siRNA administration at the time of infection with a recombinant, replication-deficient adenovirus [El-deleted adenovirus encoding beta-galactosidase (AdCMV-LacZ)], earlier and dramatically increased, and earlier ALT elevations were observed in wild-type B6 but not in B6.gzmb(-/-) NK cell-depleted mice. When a 3-fold higher dose of AdCMV-LacZ was administered to B6 mice, the coadministration of SPI-6 siRNA resulted in the early onset of lethal, acute liver failure. Of note, the accelerated clearance of AdCMV-LacZ was observed in recipients of SPI-6 siRNA. Conclusion: These results indicate that the regulated expression of SPI-6 in hepatocytes during viral infection or following noninfectious causes of liver injury protects hepatocytes against excessively vigorous granzyme B-dependent killing but may also delay immune clearance of virally infected hepatocytes.