Lead Increases Lipopolysaccharide-Induced Liver Injury through Tumor Necrosis Factor-α Overexpression by Monocytes/Macrophages: Role of Protein Kinase C and p42/44 Mitogen-Activated Protein Kinase

• Published in: Environmental health perspectives Vol. 114; no. 4; pp. 507 - 513
• Main Authors: Cheng, Yu-Jung, Yang, Bei-Chang, Liu, Ming-Yie
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences. National Institutes of Health. Department of Health, Education and Welfare 01-04-2006; National Institute of Environmental Health Sciences
• Subjects: Animals; Cell Line; Cultured cells; Dosage; Enzyme Activation; Hepatocytes; Kupffer cells; Lead - toxicity; Lipopolysaccharides - toxicity; Liver; Liver - drug effects; Liver - enzymology; Macrophages - drug effects; Macrophages - enzymology; Mice; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Monocytes - drug effects; Monocytes - enzymology; Necrosis; Peritoneal macrophages; Phosphorylation; Physical trauma; Protein Kinase C - metabolism; Protein kinases; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Tumors
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.8550

Although lead and lipopolysaccharide (LPS), both important environmental pollutants, activate cells through different receptors and participate in distinct upstream signaling pathways, Pb increases the amount of LPS-induced tumor necrosis $factor-\alpha$ ($TNF-\alpha$). We examined the cells responsible for the excess production of Pb-increased LPS-induced $TNF-\alpha$ and liver injury, and the roles of protein kinase C (PKC) and p42/44 mitogen-activated protein kinase (MAPK) in the induction of $TNF-\alpha$. Peritoneal injection of Pb alone ($100 \mu mol/kg$) or a low dose of LPS (5 mg/kg) did not affect serum $TNF-\alpha$ or liver functions in A/J mice. In contrast, coexposure to these noneffective doses of Pb plus LPS (Pb+LPS) strongly induced $TNF-\alpha$ expression and resulted in profound liver injury. Direct inhibition of $TNF-\alpha$ or functional inactivation of monocytes/macrophages significantly decreased the level of Pb+LPS-induced serum $TNF-\alpha$ and concurrently ameliorated liver injury. Pb+LPS coexposure stimulated the phosphorylation of p42/44 MAPK and the expression of $TNF-\alpha$ in CD14+ cells of cultured mouse whole blood, peritoneal macrophages, and RAW264.7 cells. Moreover, blocking PKC or MAPK effectively reduced Pb+LPS-induced $TNF-\alpha$ expression and liver injury. In summary, monocytes/macrophages were the cells primarily responsible for producing, through the PKC/MAPK pathway, the excess Pb-increased/LPS-induced $TNF-\alpha$ that caused liver injury.