초록 열기/닫기 버튼
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a proto-typic halogenated aromatic hydrocarbon (HAH), is part of its toxic effects appears to be derived from its ability to induce TNF-α production. However, the sig-naling pathway of TCDD that leads to TNF-α ex-pression has not been elucidated. In this study, we in-vestigated the signaling mechanism of TCD-induced TNF-α expression in PMA-differentiated THP-1 macrophages. TCDD induced both mRNA and protein expression of TNF-α in a dose- and time-dependent manner. αreceptor (AhR) inhibitor, prevented the TCDD-induced expression of TNF-α at both mRNA and protein levels. Genistein, a protein tyrosine kinase (PTK) inhibitor, and PD153035, an EGFR inhibitor, also blocked the in-crease of TNF-α expression by TCDD, indicating the role of EGFR in TCDD-induced TNF-α expression. On the other hand, P2, a c-Src specific inhibitor, did not affect TCDD-induced TNF-α expression. EGFR phos-treatment. TCDD-induced EGFR activation was AhR-dependent since co-treatment with α-NF pre-vented it. ERK was found to be a downstream efector of EGFR activation in the signaling pathway leading to TNF-α production after TCDD stimulation. Activation of ERK was observed from 30 min after TCDD treatment. PD98059, an inhibitor of the MEK-ERK path-way, completely prevented the TNF-α mRNA and pro-tein expression induced by TCDD, whereas inhibitors EGFR inhibitor, as well as α-NF significantly reduced ERK phosphorylation, suggesting that ERK activation by TCDD was mediated by both EGFR and AhR. These results indicate that TNF-α production by TCDD in dif-ferentiated 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 pro-posed where TCDD induces sequential activation of AhR, EGFR and ERK, leading to the increased ex-pression of TNF-α.
키워드열기/닫기 버튼
extracellular signal-regulated MAP kin-ases; macrophages; receptors, aryl hydrocarbon; re-ceptor, epidermal growth factor; tetrachlorodibenzo-dioxin; tumor necrosis factor-α
