Abstract | UNLABELLED: 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.
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Authors | Heather W Stout-Delgado, Yonas Getachew, Thomas E Rogers, Bonnie C Miller, Dwain L Thiele |
Journal | Hepatology (Baltimore, Md.)
(Hepatology)
Vol. 46
Issue 5
Pg. 1530-40
(Nov 2007)
ISSN: 1527-3350 [Electronic] United States |
PMID | 17685438
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Membrane Proteins
- Serpins
- Alanine Transaminase
- Granzymes
- Serine Endopeptidases
- Serpinb9 protein, mouse
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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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