KMID : 0620920070390040524
|
|
Experimental & Molecular Medicine 2007 Volume.39 No. 4 p.524 ~ p.534
|
|
Signaling pathway for 2,3,7,8-tetrachlorodibenzop- dioxin-induced TNF-¥á production in differentiated THP-1 human macrophages
|
|
Cheon Hyeon-Joo
Woo Young-Seok Lee Ji-Young Kim Hee-Sook Kim Hyun-Jin Cho Sung-Won Won Nam-Hee Sohn Jeong-Won
|
|
Abstract
|
|
|
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-¥á production. However, the signaling pathway of TCDD that leads to TNF-¥á expression has not been elucidated. In this study, we investigated the signaling mechanism of TCDD-induced TNF-¥á expression in PMA-differentiated THP-1 macrophages. TCDD induced both mRNA and protein expression of TNF-¥á in a dose- and time-dependent manner. ¥á-Naphthoflavone (NF), an aryl hydrocarbon receptor (AhR) inhibitor, prevented the TCDD-induced expression of TNF-¥á at both mRNA and protein levels. Genistein, a protein tyrosine kinase (PTK) inhibitor, and PD153035, an EGFR inhibitor, also blocked the increase of TNF-¥á expression by TCDD, indicating the role of EGFR in TCDD-induced TNF-¥á expression. On the other hand, PP2, a c-Src specific inhibitor, did not affect TCDD-induced TNF-¥á expression. EGFR phosphorylation was detected as early as 5 min after TCDD treatment. TCDD-induced EGFR activation was AhR-dependent since co-treatment with ¥á-NF prevented it. ERK was found to be a downstream effector of EGFR activation in the signaling pathway leading to TNF-¥á 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-¥á mRNA and protein expression induced by TCDD, whereas inhibitors of JNK and p38 MAPK had no effect. PD153035, an EGFR inhibitor, as well as ¥á-NF significantly reduced ERK phosphorylation, suggesting that ERK activation by TCDD was mediated by both EGFR and AhR. These results indicate that TNF-¥á 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-¥á.
|
|
KEYWORD
|
|
extracellular signal-regulated MAP kinases, macrophages, receptors, aryl hydrocarbon, receptor, epidermal growth factor, tetrachlorodibenzodioxin, tumor necrosis factor-¥á
|
|
FullTexts / Linksout information
|
|
|
|
Listed journal information
|
|
|
|