Histone methylation and demethylation are implicated in the transient and sustained activation of the interleukin-1β gene in murine macrophages

Macrophages play a crucial role in the development of atherosclerosis. To explore the mechanism by which macrophages attain a proinflammatory phenotype for a sustained period, we stimulated macrophages with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) and measured the interleukin-1β (IL-1β) expression. The IL-1β expression increased transiently, and its expression lasted for, at least, 1 week after the cessation of LPS and IFN-γ stimulation. At the promoter region of the IL-1β gene, the demethylation of histone H3 lysine 27 (H3K27) was significantly induced for 1 week after transient stimulation with LPS and IFN-γ. The expression of H3K27 demethylases ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) and jumonji domain-containing 3 (JMJD3) increased significantly for 1 week after transient stimulation with LPS and IFN-γ. When the UTX expression was inhibited by using small interfering RNA (siRNA) for UTX, the IL-1β expression was significantly suppressed in both transient and sustained phases, whereas siRNA for JMJD3 significantly inhibited only the sustained phase of the IL-1β expression. These results suggested that H3K27 demethylation was implicated in the transient and sustained increase in the IL-1β expression after LPS and IFN-γ stimulation.