Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-α production in differentiated THP-1 human macrophages

Hyeon Joo Cheon, Young Seok Woo, Young Lee Ji, Sook Kim Hee, Jin Kim Hyun, Sungwon Cho, Hee Won Nam, Jeongwon Sohn

Research output: Contribution to journalArticle

38 Citations (Scopus)

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-α production. However, the signaling pathway of TCDD that leads to TNF-α expression has not been elucidated. In this study, we investigated the signaling mechanism of TCDD-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. α-Naphthoflavone (NF), an aryl hydrocarbon receptor (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 increase of TNF-α expression by TCDD, indicating the role of EGFR in TCDD-induced TNF-α expression. On the other hand, PP2, a c-Src specific inhibitor, did not affect TCDD-induced TNF-α expression. EGFR phosphorylation was detected as early as 5 min after TCDD treatment. TCDD-induced EGFR activation was AhR-dependent since co-treatment with α-NF prevented it. ERK was found to be a downstream effector 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 pathway, completely prevented the TNF-α mRNA and protein expression induced by TCDD, whereas inhibitors of JNK and p38 MAPK had no effect. PD153035, an 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 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-α.

Original languageEnglish
Pages (from-to)524-534
Number of pages11
JournalExperimental and Molecular Medicine
Volume39
Issue number4
Publication statusPublished - 2007 Aug 31

Fingerprint

Macrophages
Aryl Hydrocarbon Receptors
Chemical activation
Phosphorylation
1,4-dioxin
Polychlorinated Dibenzodioxins
p38 Mitogen-Activated Protein Kinases
Messenger RNA
Halogenated Hydrocarbons
Aromatic Hydrocarbons
Proteins
MAP Kinase Signaling System
Genistein
Poisons
Mitogen-Activated Protein Kinase Kinases
Protein Kinase Inhibitors
Protein-Tyrosine Kinases

Keywords

  • Extracellular signal-regulated MAP kinases
  • Macrophages
  • Receptor, epidermal growth factor
  • Receptors, aryl hydrocarbon
  • Tetrachlorodibenzodioxin
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-α production in differentiated THP-1 human macrophages. / Cheon, Hyeon Joo; Woo, Young Seok; Ji, Young Lee; Hee, Sook Kim; Hyun, Jin Kim; Cho, Sungwon; Nam, Hee Won; Sohn, Jeongwon.

In: Experimental and Molecular Medicine, Vol. 39, No. 4, 31.08.2007, p. 524-534.

Research output: Contribution to journalArticle

Cheon, Hyeon Joo ; Woo, Young Seok ; Ji, Young Lee ; Hee, Sook Kim ; Hyun, Jin Kim ; Cho, Sungwon ; Nam, Hee Won ; Sohn, Jeongwon. / Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-α production in differentiated THP-1 human macrophages. In: Experimental and Molecular Medicine. 2007 ; Vol. 39, No. 4. pp. 524-534.
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AU - Cheon, Hyeon Joo

AU - Woo, Young Seok

AU - Ji, Young Lee

AU - Hee, Sook Kim

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