Epigenetic synergism between interleukin-4 and aryl-hydrocarbon receptor in human macrophages

Wei Ting Liao, Jian He Lu, Wei Ting Wang, Chih Hsing Hung, Chau Chyun Sheu, Shau Ku Huang

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


Abstract: The aryl hydrocarbon receptor (AhR)-ligand axis is involved in immune regulation, but its molecular basis remains to be fully elucidated. Chemokine (C-C motif) ligand 1 (CCL1) is an important chemoattractant, but how CCL1 is regulated remains to be defined. The role of AhR in regulating CCL1 expression in two major subsets of macrophage was investigated. We used a human THP-1 cell line, monocytes, and mouse peritoneal macrophages to generate M(IFN-γ/LPS) and M(IL-4) subsets, and the AhR’s ligand effect was determined by the use of a combination of chromatin immunoprecipitation, PCR, and ELISA. Upon exposure to a classical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), selective induction of CCL1 was noted only in M(IL-4), not M(IFN-γ/LPS) cells in human but not murine macrophages. This selectivity was mediated by AhR’s binding to the distal dioxin-responsive element (DRE) in the CCL1 promoter of the M(IL-4) subset, and a deletion mutant lacking the distal DRE sequence lost its activity. In contrast to the M(IFN-γ/LPS) cells, the distal DRE was devoid of tri-methylated histone 3 lysine 27 (H3K27) in M(IL-4) cells, and the addition of a H3K27 demethylase inhibitor blocked AhR-mediated CCL1 expression. Similar selectivity of CCL1 expression was also noted in monocyte-derived M(IL-4) subsets, and the level of AhR binding to distal DRE in monocytes was correlated with the levels of plasma interleukin-4 (IL-4) in 23 human subjects. These findings suggested the existence of a new regulatory epigenetic-based mechanism, wherein AhR in concert with IL-4 differentially regulated human, not murine, macrophage CCL1 response. Key message: Human CCL1 gene is selectively targeted by AhR in M(IL-4) macrophage.IL-4-induced epigenetic modification potentiates AhR-mediated CCL1 expression.This epigenetic control of CCL1 expression is not operative in murine macrophages.

Original languageEnglish
Pages (from-to)395-404
Number of pages10
JournalJournal of Molecular Medicine
Issue number4
Publication statusPublished - Apr 1 2017


  • Aryl hydrocarbon receptor
  • Chemokine C-C motif ligand 1
  • Dioxin
  • Macrophage polarization

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)


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