BACKGROUND: Whereas recent research has characterized the mechanism by which dendritic cells (DCs) induce TH1/TH17 responses, the functional specialization enabling DCs to polarize TH2 responses remains undefined. Because IL-4 is essential during TH2 responses not only by acting on CD4(+) T cells through the activation of GATA-3 but also by regulating IgE class-switching, epithelial cell permeability, and muscle contractility, we hypothesized that IL-4 could also have a role in the conditioning of DCs during TH2 responses. OBJECTIVE: We sought to analyze whether IL-4 exerts an immunomodulatory function on DCs during their differentiation, leading to their functional specialization for the induction of TH2 responses. METHODS: Monocyte-derived DCs (moDCs) conditioned by IL-4 during their differentiation (IL-4-conditioned moDCs [IL-4-moDCs]) were analyzed for TH1-polarizing/inflammatory cytokine production in response to Toll-like receptor stimulation. The acetylation level of the promoters of the genes encoding these cytokines was analyzed by using chromatin immunoprecipitation. Gene expression profiling of IL-4-moDCs was defined by using mouse genome microarrays. IL-4-moDCs were tested for their capacity to induce house dust mite-mediated allergic reactions. RESULTS: Our data suggest that IL-4 inhibits TH1-polarizing/inflammatory cytokine gene expression on IL-4-moDCs through the deacetylation of the promoters of these genes, leading to their transcriptional repression. Microarray analyses confirmed that IL-4 upregulated TH2-related genes as eosinophil-associated ribonucleases, eosinophil/basophil chemokines, and M2 genes. IL-4 licensed moDCs for the induction of TH2 responses, causing house dust mite-mediated allergic airway inflammation. CONCLUSION: This study describes a new role for IL-4 by demonstrating that moDCs are conditioned by IL-4 for the induction of TH2 responses by blocking TH1-polarizing/inflammatory cytokine production through histone hypoacetylation and upregulating TH2-related genes.