Molecular mechanisms underlying mancozeb-induced inhibition of TNF-alpha production.

Details

Serval ID
serval:BIB_DCFD8433C4C0
Type
Article: article from journal or magazin.
Collection
Publications
Title
Molecular mechanisms underlying mancozeb-induced inhibition of TNF-alpha production.
Journal
Toxicology and applied pharmacology
Author(s)
Corsini E., Viviani B., Birindelli S., Gilardi F., Torri A., Codecà I., Lucchi L., Bartesaghi S., Galli C.L., Marinovich M., Colosio C.
ISSN
0041-008X (Print)
ISSN-L
0041-008X
Publication state
Published
Issued date
15/04/2006
Peer-reviewed
Oui
Volume
212
Number
2
Pages
89-98
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Mancozeb, a polymeric complex of manganese ethylenebisdithiocarbamate with zinc salt, is widely used in agriculture as fungicide. Literature data indicate that ethylenebisdithiocarbamates (EBDTCs) may have immunomodulatory effects in humans. We have recently found in agricultural workers occupationally exposed to the fungicide mancozeb a statistically significant decrease in lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF) production in leukocytes. TNF is an essential proinflammatory cytokine whose production is normally stimulated during an infection. The purpose of this work was to establish an in vitro model reflecting in vivo data and to characterize the molecular mechanism of action of mancozeb. The human promyelocytic cell line THP-1 was used as in vitro model to study the effects of mancozeb and its main metabolite ethylenthiourea (ETU) on LPS-induced TNF release. Mancozeb, but not ETU, at non-cytotoxic concentrations (1-100 microg/ml), induced a dose- and time-dependent inhibition of LPS-induced TNF release, reflecting in vivo data. The modulatory effect observed was not limited to mancozeb but also other EBDTCs, namely zineb and ziram, showed similar inhibitory effects. Mancozeb must be added before or simultaneously to LPS in order to observe the effect, indicating that it acts on early events triggered by LPS. It is known that nuclear factor-kappaB (NF-kappaB) tightly regulates TNF transcription. We could demonstrate that mancozeb, modulating LPS-induced reactive oxygen species generation, prevented IkappaB degradation and NF-kappaB nuclear translocation, which in turn resulted in decreased TNF production. To further understand the mechanism of the effect of mancozeb on TNF transcription, THP-1 cells were transfected with NF-kappaB promoter-luciferase construct, and the effect of mancozeb on luciferase activity was measured. Cells transfected with promoter constructs containing kappaB site showed decreased LPS-induced luciferase activity relative to control after mancozeb treatment, confirming NF-kappaB binding as an intracellular target of mancozeb. Overall, this study contributes to our understanding of the mechanism underlying mancozeb-induced immunotoxicity.
Keywords
Biotransformation/drug effects, Blotting, Western, Cell Line, Cell Line, Tumor, Dose-Response Relationship, Drug, Ethylenethiourea/toxicity, Fungicides, Industrial/toxicity, Genes, Reporter, Humans, L-Lactate Dehydrogenase/metabolism, Lipopolysaccharides/pharmacology, Maneb/toxicity, NF-kappa B/metabolism, Reactive Oxygen Species/metabolism, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors/genetics, Transcription, Genetic/drug effects, Tumor Necrosis Factor-alpha/biosynthesis, Zineb/toxicity, Ziram/toxicity
Pubmed
Web of science
Create date
21/03/2019 11:29
Last modification date
20/02/2020 6:26
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