Lead increases lipopolysaccharide-induced liver-injury through tumor necrosis factor-alpha overexpression by monocytes/macrophages: role of protein kinase C and P42/44 mitogen-activated protein kinase.
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 micromol/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. alpha.
Department of Environmental and Occupational Health, Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 70428, Taiwan.
Yu-Jung
YJ
Cheng
Bei-Chang
BC
Yang
Ming-Yie
MY
Liu
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D007854:Lead / Q000633:toxicity*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D011493:Protein Kinase C / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007854:Lead; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3