Macrophage activation by factors released from acetaminophen-injured hepatocytes: Potential role of HMGB1

Journal Article · Wed Jun 15 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.04.003· OSTI ID:21587765

Dragomir, Ana-Cristina ^[1]; Laskin, Jeffrey D ^[2]

---

1. Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States)
2. Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States)

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 24 hr after treatment of mouse hepatocytes with 5 mM 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-1{alpha} and MIP-2. The effects of CM-AA on expression of COX-2, MIP-1{alpha} 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-1{alpha} 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. - Research Highlights: > These studies analyze macrophage activation by mediators released from acetaminophen-damaged hepatocytes. > Factors released from acetaminophen-injured hepatocytes induce macrophage ROS production and expression of COX-2, chemokines, and RAGE. > Hepatocyte-mediated macrophage activation involves p44/42 MAP kinase signaling. > HMGB1 is released from acetaminophen-injured hepatocytes and contributes to macrophage activation.

• OSTI ID: 21587765
• Journal Information: Toxicology and Applied Pharmacology, Vol. 253, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.04.003; PII: S0041-008X(11)00132-3; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIOXIDANTS
BROMIDES
CATALASE
DOSES
DTPA
EGTA
ESTERS
FLUORESCEIN
INFLAMMATION
LIVER
LIVER CELLS
MACROPHAGES
MESSENGER-RNA
NECROSIS
OXYGENASES
PIPERAZINES
TETRAZOLIUM
TOXICITY
ALCOHOLS
AMINO ACIDS
ANIMAL CELLS
AROMATICS
AZINES
AZOLES
BODY
BROMINE COMPOUNDS
CARBOXYLIC ACIDS
CHELATING AGENTS
CHLORIDES
CHLORINE COMPOUNDS
CONNECTIVE TISSUE CELLS
DIGESTIVE SYSTEM
DRUGS
DYES
ENZYMES
GLANDS
GLYCOLS
HALIDES
HALOGEN COMPOUNDS
HETEROCYCLIC COMPOUNDS
HYDROXY ACIDS
HYDROXY COMPOUNDS
NUCLEIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
OXIDOREDUCTASES
PATHOLOGICAL CHANGES
PEROXIDASES
PHAGOCYTES
PHENOLS
POLYPHENOLS
PROTEINS
PYRAZINES
RADIOPROTECTIVE SUBSTANCES
RESPONSE MODIFYING FACTORS
RNA
SOMATIC CELLS
SYMPTOMS
TETRAZOLES