Intrahepatic lymphocyte expression of dipeptidyl peptidase I-processed granzyme B and perforin induces hepatocyte expression of serine proteinase inhibitor 6 (Serpinb9/SPI-6)
Intrahepatic lymphocyte expression of dipeptidyl peptidase I-processed granzyme B and perforin induces hepatocyte expression of serine proteinase inhibitor 6 (Serpinb9/SPI-6)
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DOI：
10.4049/jimmunol.179.10.6561
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发表时间：
2007-11-15
影响因子：
4.4
通讯作者：
Thiele, Dwain L.
中科院分区：
文献类型：
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作者：
Stout-Delgado, Heather W.;Getachew, Yonas;Thiele, Dwain L.
人蛋白酶抑制剂 9 (PI-9/serpinB9) 和鼠类直系同源物丝氨酸蛋白酶抑制剂 6 (SPI-6/serpinb9) 是细胞内丝氨酸蛋白酶抑制剂 (serpin) 家族的成员。 PI-9 和 SPI-6 在免疫豁免细胞、APC 和 CTL 中表达，可保护这些细胞免受颗粒酶 B 的作用，并且当在肿瘤细胞或病毒感染的肝细胞中表达时，赋予对 CTL 和 NK 细胞杀伤的抵抗力。本研究旨在评估肝内淋巴细胞中颗粒酶 B 活性与肝脏 SPI-6 表达诱导之间是否存在相关性。为此，检查了 SPI-6、PI-9 和 serpinB9 同源物表达对 IFN-α 治疗的反应以及肝脏体内腺病毒感染期间的表达。在 IFN-α 刺激后和病毒感染过程中，肝脏中 SPI-6 mRNA 表达增加了 10 至 100 倍，而 SPI-8 没有显着上调，其他 PI-91serpinB9 同源物 mRNA 增加 < 5 倍。病毒感染期间 SPI-6 基因表达的增加与 NK 细胞和 CTL 的流入相关。此外，在 NK 细胞耗尽的小鼠中未观察到 IFN-α 诱导的肝细胞 SPI-6 mRNA 表达上调。使用缺乏穿孔素或无法加工或表达颗粒酶 B 的基因改造小鼠进行的其他实验表明，SPI-6 在肝细胞中选择性上调，以响应表达穿孔素和酶活性颗粒酶 B 的 NK 细胞对肝脏的浸润。
Human proteinase inhibitor 9 (PI-9/serpinB9) and the murine ortholog, serine proteinase inhibitor 6 (SPI-6/serpinb9) are members of a family of intracellular serine proteinase inhibitors (serpins). PI-9 and SPI-6 expression in immune-privileged cells, APCs, and CTLs protects these cells against the actions of granzyme B, and when expressed in tumor cells or virally infected hepatocytes, confers resistance to killing by CTL and NK cells. The present studies were designed to assess the existence of any correlation between granzyme B activity in intrahepatic lymphocytes and induction of hepatic SPI-6 expression. To this end, SPI-6, PI-9, and serpinB9 homolog expression was examined in response to IFN-alpha treatment and during in vivo adenoviral infection of the liver. SPI-6 mRNA expression increased 10- to 100-fold in the liver after IFN-a stimulation and during the course of viral infection, whereas no significant up-regulation of SPI-8 and < 5-fold increases in other PI-91serpinB9 homolog mRNAs was observed. Increased SPI-6 gene expression during viral infection correlated with influxes of NK cells and CTL. Moreover, IFN-alpha-induced up-regulation of hepatocyte SPI-6 mRNA expression was not observed in NK cell-depleted mice. Additional experiments using genetically altered mice either deficient in perforin or unable to process or express granzyme B indicated that SPI-6 is selectively up-regulated in hepatocytes in response to infiltration of the liver by NK cells that express perforin and enzymatically active granzyme B.