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National Institute of Environmental Health Sciences

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Publication Detail

Title: Macrophage activation by factors released from acetaminophen-injured hepatocytes: potential role of HMGB1.

Authors: Dragomir, Ana-Cristina; Laskin, Jeffrey D; Laskin, Debra L

Published In Toxicol Appl Pharmacol, (2011 Jun 15)

Abstract: Toxic doses of acetaminophen (AA) cause hepatocellular necrosis. Evidence suggests that activated macrophages contribute to the pathogenic process; however, the factors that activate these cells are unknown. In these studies, we assessed the role of mediators released from AA-injured hepatocytes in macrophage activation. Treatment of macrophages with conditioned medium (CM) collected 24hr after treatment of mouse hepatocytes with 5mM AA (CM-AA) resulted in increased production of reactive oxygen species (ROS). Macrophage expression of heme oxygenase-1 (HO-1) and catalase mRNA was also upregulated by CM-AA, as well as cyclooxygenase (COX)-2 and 12/15-lipoxygenase (LOX). CM-AA also upregulated expression of the proinflammatory chemokines, MIP-1α and MIP-2. The effects of CM-AA on expression of COX-2, MIP-1α and MIP-2 were inhibited by blockade of p44/42 MAP kinase, suggesting a biochemical mechanism mediating macrophage activation. Hepatocytes injured by AA were found to release HMGB1, a potent macrophage activator. This was inhibited by pretreatment of hepatocytes with ethyl pyruvate (EP), which blocks HMGB1 release. EP also blocked CM-AA induced ROS production and antioxidant expression, and reduced expression of COX-2, but not MIP-1α or MIP-2. These findings suggest that HMGB1 released by AA-injured hepatocytes contributes to macrophage activation. This is supported by our observation that expression of the HMGB1 receptor RAGE is upregulated in macrophages in response to CM-AA. These data indicate that AA-injured hepatocytes contribute to the inflammatory environment in the liver through the release of mediators such as HMGB1. Blocking HMGB1/RAGE may be a useful approach to limiting classical macrophage activation and AA-induced hepatotoxicity.

PubMed ID: 21513726 Exiting the NIEHS site

MeSH Terms: Acetaminophen/toxicity*; Analgesics, Non-Narcotic/toxicity*; Animals; Chemokine CCL2/physiology; Cyclooxygenase 2/physiology; Extracellular Signal-Regulated MAP Kinases/physiology; HMGB1 Protein/physiology*; Heme Oxygenase-1/physiology; Hepatocytes/drug effects*; Hepatocytes/metabolism; Macrophage Activation/physiology*; Male; Membrane Proteins/physiology; Mice; Mice, Inbred C57BL

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