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

AbstractUNLABELLED:
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 [E1-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(-/-) 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.
AuthorsHeather W Stout-Delgado, Yonas Getachew, Thomas E Rogers, Bonnie C Miller, Dwain L Thiele
JournalHepatology (Baltimore, Md.) (Hepatology) Vol. 46 Issue 5 Pg. 1530-40 (Nov 2007) ISSN: 1527-3350 [Electronic] United States
PMID17685438 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Membrane Proteins
  • Serpins
  • Alanine Transaminase
  • Granzymes
  • Serine Endopeptidases
  • Serpinb9 protein, mouse
Topics
  • Adenoviridae Infections (blood)
  • Alanine Transaminase (blood)
  • Animals
  • Apoptosis (physiology)
  • Granzymes (physiology)
  • Hepatitis, Viral, Animal (metabolism)
  • Hepatocytes (enzymology)
  • Killer Cells, Natural (physiology)
  • Liver (enzymology, virology)
  • Membrane Proteins (metabolism)
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Serine Endopeptidases (metabolism)
  • Serpins (metabolism)
  • T-Lymphocytes, Cytotoxic (physiology)

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