Abstract
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 language | English |
|---|---|
| Pages (from-to) | 395-404 |
| Number of pages | 10 |
| Journal | Journal of Molecular Medicine |
| Volume | 95 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 1 2017 |
| Externally published | Yes |
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Keywords
- Aryl hydrocarbon receptor
- Chemokine C-C motif ligand 1
- Dioxin
- Macrophage polarization
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
- Genetics(clinical)
Cite this
Epigenetic synergism between interleukin-4 and aryl-hydrocarbon receptor in human macrophages. / Liao, Wei Ting; Lu, Jian He; Wang, Wei Ting; Hung, Chih Hsing; Sheu, Chau Chyun; Huang, Shau Ku.
In: Journal of Molecular Medicine, Vol. 95, No. 4, 01.04.2017, p. 395-404.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Epigenetic synergism between interleukin-4 and aryl-hydrocarbon receptor in human macrophages
AU - Liao, Wei Ting
AU - Lu, Jian He
AU - Wang, Wei Ting
AU - Hung, Chih Hsing
AU - Sheu, Chau Chyun
AU - Huang, Shau Ku
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
KW - Aryl hydrocarbon receptor
KW - Chemokine C-C motif ligand 1
KW - Dioxin
KW - Macrophage polarization
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U2 - 10.1007/s00109-016-1493-1
DO - 10.1007/s00109-016-1493-1
M3 - Article
C2 - 27888289
AN - SCOPUS:84997077999
VL - 95
SP - 395
EP - 404
JO - Journal of Molecular Medicine
JF - Journal of Molecular Medicine
SN - 0946-2716
IS - 4
ER -