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

摘要

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 concurrendy 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-alphalpha 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.