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


CONCLUSIONS
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.
Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
Heather W
HW
Stout-Delgado
Yonas
Y
Getachew
Thomas E
TE
Rogers
Bonnie C
BC
Miller
Dwain L
DL
Thiele
D000257:Adenoviridae Infections / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053804:Granzymes / Q000502:physiology*; D006524:Hepatitis, Viral, Animal / Q000378:metabolism*; D022781:Hepatocytes / Q000201:enzymology*; D007694:Killer Cells, Natural / Q000502:physiology*; D008099:Liver / Q000201:enzymology / Q000821:virology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012697:Serine Endopeptidases / Q000378:metabolism*; D015843:Serpins / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*
D008565:Membrane Proteins; D015843:Serpins; D000410:Alanine Transaminase; D053804:Granzymes; D012697:Serine Endopeptidases; C106610:Serpinb9 protein, mouse