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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2007-10-15
pubmed:abstractText
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a prototypic halogenated aromatic hydrocarbon (HAH), is known as one of the most potent toxicants. At least a part of its toxic effects appears to be derived from its ability to induce TNF-alpha production. However, the signaling pathway of TCDD that leads to TNF-alpha expression has not been elucidated. In this study, we investigated the signaling mechanism of TCDD-induced TNF-alpha expression in PMA-differentiated THP-1 macrophages. TCDD induced both mRNA and protein expression of TNF-alpha in a dose- and time-dependent manner. Alpha-naphthoflavone (NF), an aryl hydrocarbon receptor (AhR) inhibitor, prevented the TCDD-induced expression of TNF-alpha at both mRNA and protein levels. Genistein, a protein tyrosine kinase (PTK) inhibitor, and PD153035, an EGFR inhibitor, also blocked the increase of TNF-alpha expression by TCDD, indicating the role of EGFR in TCDD-induced TNF-alpha expression. On the other hand, PP2, a c-Src specific inhibitor, did not affect TCDD-induced TNF-alpha expression. EGFR phosphorylation was detected as early as 5 min after TCDD treatment. TCDD-induced EGFR activation was AhR-dependent since co-treatment with alpha-NF prevented it. ERK was found to be a downstream effector of EGFR activation in the signaling pathway leading to TNF-alpha production after TCDD stimulation. Activation of ERK was observed from 30 min after TCDD treatment. PD98059, an inhibitor of the MEK-ERK pathway, completely prevented the TNF-alpha mRNA and protein expression induced by TCDD, whereas inhibitors of JNK and p38 MAPK had no effect. PD153035, an EGFR inhibitor, as well as alpha-NF significantly reduced ERK phosphorylation, suggesting that ERK activation by TCDD was mediated by both EGFR and AhR. These results indicate that TNF-alpha production by TCDD in differentiated THP-1 macrophages is AhR-dependent and involves activation of EGFR and ERK, but not c-Src, JNK, nor p38 MAPK. A signaling pathway is proposed where TCDD induces sequential activation of AhR, EGFR and ERK, leading to the increased expression of TNF-alpha.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/4-((3-bromophenyl)amino)-6,7-dimetho..., http://linkedlifedata.com/resource/pubmed/chemical/AG 1879, http://linkedlifedata.com/resource/pubmed/chemical/Benzoflavones, http://linkedlifedata.com/resource/pubmed/chemical/Genistein, http://linkedlifedata.com/resource/pubmed/chemical/Hazardous Substances, http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines, http://linkedlifedata.com/resource/pubmed/chemical/Quinazolines, http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger, http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Epidermal Growth Factor, http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Aryl Hydrocarbon, http://linkedlifedata.com/resource/pubmed/chemical/Tetrachlorodibenzodioxin, http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha, http://linkedlifedata.com/resource/pubmed/chemical/alpha-naphthoflavone, http://linkedlifedata.com/resource/pubmed/chemical/src-Family Kinases
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1226-3613
pubmed:author
pubmed:issnType
Print
pubmed:day
31
pubmed:volume
39
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
524-34
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:17934341-Animals, pubmed-meshheading:17934341-Benzoflavones, pubmed-meshheading:17934341-Cell Differentiation, pubmed-meshheading:17934341-Cell Line, Tumor, pubmed-meshheading:17934341-Enzyme Activation, pubmed-meshheading:17934341-Genistein, pubmed-meshheading:17934341-Hazardous Substances, pubmed-meshheading:17934341-Humans, pubmed-meshheading:17934341-MAP Kinase Signaling System, pubmed-meshheading:17934341-Macrophages, pubmed-meshheading:17934341-Mice, pubmed-meshheading:17934341-Phosphorylation, pubmed-meshheading:17934341-Pyrimidines, pubmed-meshheading:17934341-Quinazolines, pubmed-meshheading:17934341-RNA, Messenger, pubmed-meshheading:17934341-Receptor, Epidermal Growth Factor, pubmed-meshheading:17934341-Receptors, Aryl Hydrocarbon, pubmed-meshheading:17934341-Signal Transduction, pubmed-meshheading:17934341-Tetrachlorodibenzodioxin, pubmed-meshheading:17934341-Tumor Necrosis Factor-alpha, pubmed-meshheading:17934341-src-Family Kinases
pubmed:year
2007
pubmed:articleTitle
Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-alpha production in differentiated THP-1 human macrophages.
pubmed:affiliation
Department of Biochemistry, Korean Institute of Molecular Medicine and Nutrition, Korea University College of Medicine, Seoul 136-705, Korea.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't