The role of serpinb9/serine protease inhibitor 6 in preventing granzyme B-dependent hepatotoxicity

Heather W. Stout-Delgado, Yonas Getachew, Thomas E. Rogers, Bonnie C. Miller, Dwain L Thiele

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

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 C57B1/6J (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 [E1-deleted adenovirus encoding β-galactosidase (AdCMV-LacZ)], earlier and dramatically increased, and earlier ALT elevations were observed in wild-type B6 but not in B6.gzmb-/- or 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.

Original languageEnglish (US)
Pages (from-to)1530-1540
Number of pages11
JournalHepatology
Volume46
Issue number5
DOIs
StatePublished - Nov 1 2007

ASJC Scopus subject areas

  • Hepatology

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