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

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.