Yonas Getachew1, Frank A Cusimano2, Laura P James3, Dwain L Thiele2. 1. Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9151, USA. Electronic address: yonas.getachew@utsouthwestern.edu. 2. Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9151, USA. 3. Department of Pediatrics, University of Arkansas, Little Rock, AR, USA.
Abstract
UNLABELLED: The role of the immune system, specifically NK, NKT and CD3 cells, in acetaminophen (APAP) induced liver injury remains inconsistently defined. In the present study, wild type (C57BL/6J) mice and granzyme B deficient (GrB -/-) mice were treated with acetaminophen to assess the role of the immune system in acute liver injury. Doses of acetaminophen that induced sub lethal liver injury in wild type mice unexpectedly produced fatal hepatotoxicity in granzyme B deficient (GrB -/-) mice. Analysis revealed that GrB -/- mice had an increased population of intrahepatic CD3 (+), CD4 (-), and CD8 (-) lymphocytes expressing the CD69 activation marker and Fas ligand. Depletion of these cells in the GrB -/- and wild type mice made them less susceptible to APAP injury, while depletion of NK1.1 (+) cells or both CD4 (+) and CD8 (+) T cells failed to provide the same hepatoprotection. Transfer of the GrB -/- IHLs further exacerbated liver injury and increased mortality in wild type mice but not in LRP/LPR mice, lacking fas expression. CONCLUSIONS: Acetaminophen toxicity is enhanced by the presence of activated, FasL expressing intrahepatic CD3 (+), CD4 (-), CD8 (-), NK1.1 (-) T cells. Depletion of these cells from GrB -/- mice and wild type mice greatly reduces mortality and improves the course of liver injury recovery. Published by Elsevier Inc.
UNLABELLED: The role of the immune system, specifically NK, NKT and CD3 cells, in acetaminophen (APAP) induced liver injury remains inconsistently defined. In the present study, wild type (C57BL/6J) mice and granzyme B deficient (GrB -/-) mice were treated with acetaminophen to assess the role of the immune system in acute liver injury. Doses of acetaminophen that induced sub lethal liver injury in wild type mice unexpectedly produced fatal hepatotoxicity in granzyme B deficient (GrB -/-) mice. Analysis revealed that GrB -/- mice had an increased population of intrahepatic CD3 (+), CD4 (-), and CD8 (-) lymphocytes expressing the CD69 activation marker and Fas ligand. Depletion of these cells in the GrB -/- and wild type mice made them less susceptible to APAP injury, while depletion of NK1.1 (+) cells or both CD4 (+) and CD8 (+) T cells failed to provide the same hepatoprotection. Transfer of the GrB -/- IHLs further exacerbated liver injury and increased mortality in wild type mice but not in LRP/LPRmice, lacking fas expression. CONCLUSIONS:Acetaminophentoxicity is enhanced by the presence of activated, FasL expressing intrahepatic CD3 (+), CD4 (-), CD8 (-), NK1.1 (-) T cells. Depletion of these cells from GrB -/- mice and wild type mice greatly reduces mortality and improves the course of liver injury recovery. Published by Elsevier Inc.
Authors: Kenneth L Muldrew; Laura P James; Leslie Coop; Sandra S McCullough; Howard P Hendrickson; Jack A Hinson; Philip R Mayeux Journal: Drug Metab Dispos Date: 2002-04 Impact factor: 3.922