PMID- 15578514
OWN - NLM
STAT- MEDLINE
DCOM- 20050104
LR  - 20220408
IS  - 0016-5085 (Print)
IS  - 0016-5085 (Linking)
VI  - 127
IP  - 6
DP  - 2004 Dec
TI  - Innate immune system plays a critical role in determining the progression and 
      severity of acetaminophen hepatotoxicity.
PG  - 1760-74
AB  - 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.
FAU - Liu, Zhang-Xu
AU  - Liu ZX
AD  - Research Center for Liver Disease, Department of Medicine, Keck School of 
      Medicine, University of Southern California, Los Angeles, California 90033, USA. 
      zxliu@usc.edu
FAU - Govindarajan, Sugantha
AU  - Govindarajan S
FAU - Kaplowitz, Neil
AU  - Kaplowitz N
LA  - eng
GR  - DK30312/DK/NIDDK NIH HHS/United States
GR  - K01DK67149/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (Analgesics, Non-Narcotic)
RN  - 0 (Cytokines)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 362O9ITL9D (Acetaminophen)
SB  - IM
MH  - Acetaminophen/*adverse effects/toxicity
MH  - Analgesics, Non-Narcotic/*adverse effects/toxicity
MH  - Animals
MH  - Cytokines/biosynthesis/pharmacology
MH  - Disease Progression
MH  - Female
MH  - Humans
MH  - Killer Cells, Natural/*immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Receptors, Antigen, T-Cell/immunology
MH  - Severity of Illness Index
EDAT- 2004/12/04 09:00
MHDA- 2005/01/05 09:00
CRDT- 2004/12/04 09:00
PHST- 2004/12/04 09:00 [pubmed]
PHST- 2005/01/05 09:00 [medline]
PHST- 2004/12/04 09:00 [entrez]
AID - S0016508504015549 [pii]
AID - 10.1053/j.gastro.2004.08.053 [doi]
PST - ppublish
SO  - Gastroenterology. 2004 Dec;127(6):1760-74. doi: 10.1053/j.gastro.2004.08.053.