Cytokines and Toxicity in Acetaminophen Overdose

James, Laura P.; Simpson, Pippa; Farrar, Henry C.; Kearns, Gregory L.; Wasserman, Gary S.; Blumer, Jeffrey L.; Reed, Michael D.; Sullivan, Janice E.; Hinson, Jack

doi:10.1177/0091270005280296

Cited by 81 publications

(41 citation statements)

References 33 publications

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“…2C), consistent with reduced serum ALT levels. Inflammatory cytokine levels are increased in APAP-induced liver injury and seem to be correlated with the severity of injury (James et al, 2005). In agreement with decreased liver injury, we observed decreased inflammatory cytokine expression in Mlk(Ϫ/Ϫ) mice treated with APAP, compared with WT mice (Fig.…”

Section: Resultssupporting

confidence: 84%

Critical Role for Mixed-Lineage Kinase 3 in Acetaminophen-Induced Hepatotoxicity

2012

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c-Jun NH 2 -terminal kinase (JNK) activation plays a major role in acetaminophen (APAP)-induced hepatotoxicity. However, the exact mechanism of APAP-induced JNK activation is incompletely understood. It has been established that apoptosis signal-regulating kinase 1 (ASK1) regulates the late phase of APAP-induced JNK activation, but the mitogen-activated protein kinase kinase kinase that mediates the initial phase of APAP-induced JNK activation has not been identified. Oxidative stress produced during APAP metabolism causes JNK activation, which promotes mitochondrial dysfunction and results in the amplification of oxidative stress. Therefore, inhibition of the initial phase of JNK activation may be key to protection against APAP-induced liver injury. The goal of this study was to determine whether mixed-lineage kinase 3 (MLK3) mediates the initial, ASK1-independent phase of APAP-induced JNK activation and thus promotes drug-induced hepatotoxicity. We found that MLK3 was activated by oxidative stress and was required for JNK activation in response to oxidative stress. Loss of MLK3 attenuated APAP-induced JNK activation and hepatocyte death in vitro, independent of receptor-interacting protein 1. Moreover, JNK and glycogen synthase kinase 3␤ activation was significantly attenuated, and Mcl-1 degradation was inhibited in APAP-treated MLK3-knockout mice. Furthermore, we showed that loss of MLK3 increased expression of glutamate cysteine ligase, accelerated hepatic GSH recovery, and decreased production of reactive oxygen species after APAP treatment. MLK3-deficient mice were significantly protected from APAP-induced liver injury, compared with wildtype mice. Together, these studies establish a novel role for MLK3 in APAP-induced JNK activation and hepatotoxicity, and they suggest MLK3 as a possible target in the treatment of APAP-induced liver injury.

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Section: Resultssupporting

confidence: 84%

Critical Role for Mixed-Lineage Kinase 3 in Acetaminophen-Induced Hepatotoxicity

2012

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“…The actions of cytokines, inflammatory mediators, and reactive oxidant species have gained increasing prominence for their roles in acetaminophen-induced liver injury (Dambach et al, 2005;James et al, 2005b). Acute phase response proteins that we found in serum suggested we search for other serum cytokines and chemokines, particularly since these are typically below detection limits for staining in two-dimensional gels.…”

Section: Discussionmentioning

confidence: 97%

Alterations in the Rat Serum Proteome during Liver Injury from Acetaminophen Exposure

Merrick¹,

Bruno²,

Madenspacher³

et al. 2006

J Pharmacol Exp Ther

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Changes in the serum proteome were identified during early, fulminant, and recovery phases of liver injury from acetaminophen in the rat. Male F344 rats received a single, noninjury dose or a high, injury-producing dose of acetaminophen for evaluation at 6 to 120 h. Two-dimensional gel electrophoresis of immunodepleted serum separated approximately 800 stained proteins per sample from which differentially expressed proteins were identified by mass spectrometry. Serum alanine aminotransferase/aspartate aminotransferase levels and histopathology revealed the greatest liver damage at 24 and 48 h after high-dose acetaminophen corresponding to the time of greatest serum protein alterations. After 24 h, 68 serum proteins were significantly altered of which 23 proteins were increased by Ͼ5-fold and 20 proteins were newly present compared with controls. Only minimal changes in serum proteins were noted at the low dose without any histopathology. Of the 54 total protein isoforms identified by mass spectrometry, gene ontology processes for 38 unique serum proteins revealed involvement of acute phase response, coagulation, protein degradation, intermediary metabolism, and various carrier proteins. Elevated serum tumor necrosis factor-␣ from 24 to 48 h suggested a mild inflammatory response accompanied by increased antioxidant capability demonstrated by increased serum catalase activity. Antibody array and enzyme-linked immunosorbent assay analyses also showed elevation in the chemokine monocyte chemoattractant protein-1 and the metalloprotease inhibitor tissue inhibitor of metalloproteinases-1 during this same period of liver injury. This study demonstrates that serum proteome alterations probably reflect both liver damage and a concerted, complex response of the body for organ repair and recovery during acute hepatic injury.

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“…Mice with HIF-1␣-deficient monocytes produced less TNF␣, IL-6, IL-12, IL-1␣, and IL-1␤ in response to lipopolysaccharide compared with wild-type animals (Peyssonnaux et al, 2007). In human patients, large plasma concentrations of IL-6, IL-8, and monocyte chemotactic protein-1 correlated with the severity of liver injury caused by APAP overdose (James et al, 2005). Furthermore, APAP overdose increased plasma concentrations of IL-1␤, IL-6, KC, monocyte chemotactic protein-1, MIP-2, and TNF␣ in mice (Ishida et al, 2002(Ishida et al, , 2004Masubuchi et al, 2003).…”

mentioning

confidence: 94%

“…Mediators released from necrotic hepatocytes activate Kupffer cells, recruit and activate polymorphonuclear neutrophils (PMNs), and consequently produce cytokines that influence APAP-induced hepatocellular injury (James et al, 2005;Cover et al, 2006). The role of PMNs in APAP hepatotoxicity remains controversial, with evidence both for and against a contribution of PMNs to injury progression (Jaeschke, 2008).…”

Section: Introductionmentioning

confidence: 99%