Lead Increases Lipopolysaccharide-Induced Liver-Injury Through Tumor Necrosis Factor- Overexpression by Monocytes/Macrophages: Role of Protein Kinase C and P42/44 Mitogen-Activated Protein Kinase Yu-Jung Cheng,1,2 Bei-Chang Yang,2,3 and Ming-Yie
Liu1,2 1Department of Environmental and Occupational Health, 2Institute
of Basic Medical Sciences, and 3Department of Microbiology and Immunology,
National Cheng Kung University Medical College, Tainan, Taiwan Abstract 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- (TNF-) . We examined the cells responsible for the excess production of Pb-increased LPS-induced TNF- and liver injury, and the roles of protein kinase C (PKC) and p42/44 mitogen-activated protein kinase (MAPK) in the induction of TNF-. Peritoneal injection of Pb alone (100 µmol/kg) or a low dose of LPS (5 mg/kg) did not affect serum TNF- or liver functions in A/J mice. In contrast, coexposure to these noneffective doses of Pb plus LPS (Pb+LPS) strongly induced TNF- expression and resulted in profound liver injury. Direct inhibition of TNF- or functional inactivation of monocytes/macrophages significantly decreased the level of Pb+LPS-induced serum TNF- and concurrently ameliorated liver injury. Pb+LPS coexposure stimulated the phosphorylation of p42/44 MAPK and the expression of TNF- 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- 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- that caused liver injury. Key words: lead, lipopolysaccharide, liver injury, monocytes/macrophage, p42/44 mitogen-activated protein kinase, protein kinase C, tumor necrosis factor-. Environ Health Perspect 114: 507-513 (2006) . doi:10.1289/ehp.8550 available via http://dx.doi.org/ [Online 10 November 2005]
Address correspondence to B.-C. Yang, Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 70428, Taiwan. Telephone: 886-6-235-3535 Ext. 5637. Fax: 886-6-208-2705. E-mail: y1357@mail.ncku.edu.tw We thank S.-T. Wang for comments on statistical analysis and B. Franke for editorial assistance. This study was supported in part by grant NSC-94-2211-E-006-090 to M.-Y.L. (co-correspondence) and grant NSC-94-2314-B-006-050 to B.-C.Y. from the National Science Council, Taiwan. The authors declare they have no competing financial interests. Received 30 July 2005 ; accepted 9 November 2005. The full version of this article is available for free in HTML or PDF formats. |