Lead increases lipopolysaccharide-induced liver injury through tumor necrosis factor-α overexpression by monocytes/macrophages: Role of protien kinase C and p42/44 mitogen-activated protein kinase

研究成果: Article同行評審

29 引文 斯高帕斯(Scopus)

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-à (TNF-α). We examined the cells responsible for the excess production of Pb-increased LPS-induced TNF-α and liver injury, and the roles of protein kinase C (PKC) and p42/44 mitogen-activated protein kinase (MAPK) in the induction of TNF-α. Peritoneal injection of Pb alone (100 μmol/kg) or a low dose of LPS (5 mg/kg) did not affect serum TNF-α or liver functions in A/J mice. In contrast, coexposure to these noneffective doses of Pb plus LPS (Pb+LPS) strongly induced TNF-α expression and resulted in profound liver injury. Direct inhibition of TNF-α or functional inactivation of monocytes/ macrophages significantly decreased the level of Pb+LPS-induced serum TNF-α and concurrently ameliorated liver injury. Pb+LPS coexposure stimulated the phosphorylation of p42/44 MAPK and the expression of TNF-α 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-α 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-α that caused liver injury.

原文English
頁(從 - 到)507-513
頁數7
期刊Environmental Health Perspectives
114
發行號4
DOIs
出版狀態Published - 2006 四月

All Science Journal Classification (ASJC) codes

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

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