Using a focused array, we demonstrated that IFN-γ or IL-4 modulate the mRNA expression of at least seven epigenetic regulators in human blood monocyte-derived macrophages, independently of any effects on cell proliferation. CIITA, KDM6B, and NCOA1 showed increased mRNA expression within 6 h of stimulation, whereas KAT2A, PRMT7, SETD6, and SMYD3 showed decreased expression that required at least 18 h of treatment. The effects were confirmed at the level of protein for SMYD3. Based on similar effects of growth factor depletion or overexpression of p27kip1, we concluded that IFN-γ or IL-4 decreased expression of AURKB, ESCO2, SUV39H1 and WHSC1 mRNA and AUKB activity, at least partly, as a consequence of cell cycle arrest at the G1/S checkpoint. Furthermore, this decreased expression could be reversed by overexpression of E2F1, which is known from published chromatin immunoprecipitation (ENCODE) studies to bind directly to the relevant promoter regions. These data expand the list of epigenetic regulators the expression of which is regulated by IFN-γ and IL-4. As a first step to establishing whether these changes impact on macrophage phenotype, we demonstrated by pharmacological inhibition and shRNA silencing that KDM6B participates in a subset of the divergent gene expression changes in response to IFN-γ and IL-4.