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
N1 - Funding Information:
This work was supported by the National Health Research Institutes (NHRI-100A1-PDCO-03000001), Ministry of Science and Technology (MOST104-2314-B-037-047), and Kaohsiung Medical University (KMU-TP-104A10), Taiwan. All authors were involved in writing the article or revising it critically for important intellectual content, and approved the final version to be published. Dr. Liao WT and Huang SK had full access to all of the data in the study and take responsibility for the accuracy of the data. Wei-Ting Liao: Study design, experimental design/processing, manuscript writing. Jian-He Lu: Experimental processing (molecular). Wei-Ting Wang: Experimental processing (clinical). Chih-Hsing Hung: Providing clinical samples and interpreting the results. Chau-Chyun Sheu: Providing clinical samples. Shau-Ku Huang: Study design, experimental design, manuscript writing.
Publisher Copyright:
© 2016, Springer-Verlag Berlin Heidelberg.
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 - Clinical Investigator
JF - Clinical Investigator
SN - 0946-2716
IS - 4
ER -