title: Lead ions abrogate lipopolysaccharide-induced nitric monoxide toxicity by reducing the expression of STAT1 and iNOS.
abstract: Lead is a widespread environmental pollutant and the highly poisonous metal compromises multiple organs in the body. Among other tissues and cells, lead ions (Pb(2+)) can affect macrophages and microglia cells. The present study observed a concentration-dependent protection of BV-2 microglia and RAW 264.7 macrophages by Pb(2+) against lipopolysaccharide (LPS)-induced toxicity. Both cell lines are potent producers of two substances that have previously been shown to mediate cytotoxic effects of LPS. These are the pro-inflammatory cytokine tumor necrosis factor (TNF)-α and nitric monoxide (NO), which creates nitrosative stress, hampering the distribution of invading pathogens and tumor cells. While the expression of TNF-α was unaffected by Pb(2+), the production of NO was significantly inhibited. Moreover, blocking NO synthesis by low molecular weight inhibitors prevented LPS-mediated toxicity, confirming the role of NO in these events. Pb(2+) exposure led to a downregulation of LPS-induced expression of the transcription factor STAT1, which is involved in iNOS transcription. Moreover, iNOS mRNA and protein levels were reduced in the presence of Pb(2+), explaining the reduced formation of NO and a subsequent increase of cellular viability in vitro. In vivo, the effect might limit collateral damage caused by excessive NO production, but also impair the efficiency of NO as a central mediator of the defense against various pathogens.
authors.affiliation: Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Dörpinghaus
authors.affiliation: Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Brieger
authors.affiliation: Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Panichkina
authors.affiliation: Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Rink
authors.affiliation: Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany; Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Gustav-Meyer-Allee 25, D-13355 Berlin, Germany. Electronic address: Haase@TU-Berlin.de.
authors.forename: Hajo
authors.initials: H
authors.lastname: Haase
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007477:Ions / Q000494:pharmacology; D007854:Lead / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis / Q000633:toxicity*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D007477:Ions; D008070:Lipopolysaccharides; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014409:Tumor Necrosis Factor-alpha; D007854:Lead; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II
keywords: LPS toxicity; Lead; Macrophages; Microglia; Nitric monoxide; TNF