{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:23:33Z","timestamp":1787163813414,"version":"build-2736575974"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2861,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01-DK53933"],"award-info":[{"award-number":["R01-DK53933"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2007,11]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>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\u2013dependent cytotoxic effector mechanisms in the liver. SPI-6\u2013specific small interfering RNA (siRNA) administration to C57Bl\/6J (B6) mice elicited transient alanine aminotransferase (ALT) elevations that were not observed in either granzyme B\u2013deficient B6 (B6.<\/jats:bold>\n                      <jats:bold>gzmb<\/jats:bold>\n                      <jats:bold>\u2212\/\u2212) or natural killer (NK) cell\u2013depleted 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 \u03b2-galactosidase (AdCMV<\/jats:bold>\n                      -\n                      <jats:bold>LacZ<\/jats:bold>\n                      <jats:bold>)], earlier and dramatically increased, and earlier ALT elevations were observed in wild-type B6 but not in B6.<\/jats:bold>\n                      <jats:bold>gzmb<\/jats:bold>\n                      <jats:bold>\u2212\/\u2212 or NK cell\u2013depleted mice. When a 3-fold higher dose of AdCMV<\/jats:bold>\n                      -\n                      <jats:bold>LacZ<\/jats:bold>\n                      <jats:bold>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<\/jats:bold>\n                      -\n                      <jats:bold>LacZ<\/jats:bold>\n                      <jats:bold>was observed in recipients of SPI-6 siRNA.<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>\n                      <jats:bold>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\u2013dependent killing but may also delay immune clearance of virally infected hepatocytes.<\/jats:bold>\n                    <\/jats:p>\n                  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