title: Arsenic increases lipopolysaccharide-dependent expression of interleukin-8 gene by stimulating a redox-sensitive pathway that strengthens p38-kinase activation.
abstract: Inorganic arsenic is an immunotoxic metalloid that causes or exacerbates deleterious inflammatory states. Notably, arsenic can increase inflammation-related gene expression induced by lipopolysaccharide (LPS) in monocytes/macrophages. Molecular mechanisms mediating such effects remain however poorly understood. In the present study, we determined molecular basis of arsenic trioxide (ATO) effects on LPS-dependent expression of interleukin-8 (IL-8) gene in human monocytic cells. Pre-treatment with non cytotoxic concentrations of ATO for 48h increase IL-8 gene expression induced by LPS in monocytic U937 cells and in some, but not all, primary cultures of blood monocytes. Actinomycin D blocks induction of IL-8 mRNA levels in LPS-stimulated U937 cells pre-treated or not with ATO, which suggests that the metalloid strengthens LPS-dependent transcriptional regulation of IL-8 expression. ATO increases LPS-dependent expression of IL-8 by enhancing p38-kinase activity induced by LPS in U937 cells. This increment of LPS-dependent p38-kinase activity is caused by the ATO-related production of reactive oxygen species (ROS) and the subsequent activation of the tyrosine kinase Src. The antioxidant N-acetylcysteine almost totally inhibits ROS production and Src kinase activation in ATO-pre-treated cells. In addition, it markedly prevents the increase of both p38-kinase phosphorylation and IL-8 gene expression in LPS-stimulated cells pre-treated with ATO. Finally, as observed with the metalloid, pre-treatment of U937 cells with hydrogen peroxide markedly increases LPS-dependent expression of IL-8 gene. In conclusion, our study demonstrates that ATO increases LPS-dependent expression of the inflammatory IL-8 gene by strengthening the p38 kinase activity induced by LPS through stimulation of a ROS/Src kinase signalling pathway.
authors.affiliation: Institut de Recherche sur la Santé, l'Environnement et le Travail (IRSET), EA-4427 Signalisation et Réponses aux Agents Infectieux et Chimiques, Université de Rennes 1, 2 avenue du Professeur Léon Bernard, 35043 Rennes, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bourdonnay
authors.forename: Claudie
authors.initials: C
authors.lastname: Morzadec
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
authors.forename: Laurent
authors.initials: L
authors.lastname: Vernhet
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D010084:Oxidation-Reduction; D010087:Oxides / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014118:Toxins, Biological / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*
chemical_list: D001152:Arsenicals; D016209:Interleukin-8; D008070:Lipopolysaccharides; D010087:Oxides; D014118:Toxins, Biological; D048051:p38 Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide