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Inflammation and drug hepatotoxicity: Aggravation of injury or clean‐up mission?
Author(s) -
Jaeschke Hartmut,
Cover Cathleen,
Bajt Mary Lynn
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20694
Subject(s) - liver injury , chemokine , natural killer t cell , natural killer cell , cytokine , immunology , interferon gamma , fas ligand , inflammation , biology , pharmacology , t cell , apoptosis , immune system , cytotoxic t cell , programmed cell death , in vitro , biochemistry
BACKGROUND & AIMS Inflammatory mediators released by nonparenchymal inflammatory cells in the liver have been implicated in the progression of acetaminophen (APAP) hepatotoxicity. Among hepatic nonparenchymal inflammatory cells, we examined the role of the abundant natural killer (NK) cells and NK cells with T‐cell receptors (NKT cells) in APAP‐induced liver injury. METHODS C57BL/6 mice were administered a toxic dose of APAP intraperitoneally to cause liver injury with or without depletion of NK and NKT cells by anti‐NK1.1 monoclonal antibody (MAb). Serum alanine transaminase (ALT) levels, liver histology, hepatic leukocyte accumulation, and cytokine/chemokine expression were assessed. RESULTS Compared with APAP‐treated control mice, depletion of both NK and NKT cells by anti‐NK1.1 significantly protected mice from APAP‐induced liver injury, as evidenced by decreased serum ALT level, improved survival of mice, decreased hepatic necrosis, inhibition of messenger RNA (mRNA) expression for interferon‐gamma (IFN‐gamma), Fas ligand (FasL), and chemokines including KC (Keratinocyte‐derived chemokine); MIP‐1 alpha (macrophage inflammatory protein‐1 alpha); MCP‐1 (monocyte chemoattractant protein‐1); IP‐10 (interferon‐inducible protein); Mig (monokine induced by IFN‐gamma) and decreased neutrophil accumulation in the liver. Hepatic NK and NKT cells were identified as the major source of IFN‐gamma by intracellular cytokine staining. APAP induced much less liver injury in Fas‐deficient (lpr) and FasL‐deficient (gld) mice compared with that in wild‐type mice. CONCLUSIONS NK and NKT cells play a critical role in the progression of APAP‐induced liver injury by secreting IFN‐gamma, modulating chemokine production and accumulation of neutrophils, and up‐regulating FasL expression in the liver, all of which may promote the inflammatory response of liver innate immune system, thus contributing to the severity and progression of liver injury downstream of the metabolism of APAP and depletion of reduced glutathione (GSH) in hepatocytes.