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Intrahepatic Lymphocyte Expression of Dipeptidyl Peptidase I-Processed Granzyme B and Perforin Induces Hepatocyte Expression of Serine Proteinase Inhibitor 6 (Serpinb9/SPI-6)¹

Heather W. Stout-Delgado^*,, Yonas Getachew^*, Bonnie C. Miller^*, and Dwain L. Thiele^2,*,

^* Department of Internal Medicine, Division of Digestive and Liver Diseases and Immunology Graduate Program, University of Texas Southwestern Medical Center, Dallas TX 75390

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- treatment and during in vivo adenoviral infection of the liver. SPI-6 mRNA expression increased 10- to 100-fold in the liver after IFN- stimulation and during the course of viral infection, whereas no significant up-regulation of SPI-8 and <5-fold increases in other PI-9/serpinB9 homolog mRNAs was observed. Increased SPI-6 gene expression during viral infection correlated with influxes of NK cells and CTL. Moreover, IFN--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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by National Institutes of Health Grant 5RO1 DK53933.

² Address correspondence and reprint requests to Dr. Dwain L. Thiele, Department of Internal Medicine, 5323 Harry Hines Boulevard, Dallas, TX 75390-9030. E-mail address: dwain.thiele{at}utsouthwestern.edu

³ Abbreviations used in this paper: DPPI, dipeptidyl peptidase; PI-9, proteinase inhibitor 9; OPU, optical particle unit; SPI-6, serine proteinase inhibitor 6; BLT, N--benzyloxy-carbonyl-L-lysine thiobenzyl.

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