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.
Stout-Delgado
Heather W
HW
Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
Getachew
Yonas
Y
Rogers
Thomas E
TE
Miller
Bonnie C
BC
Thiele
Dwain L
DL
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