IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte-derived dendritic cell differentiation through histone hypoacetylation

Abstract

Background: Whereas recent research has characterized the mechanism by which dendritic cells (DCs) induce T(H)1/T(H)17 responses, the functional specialization enabling DCs to polarize T(H)2 responses remains undefined. Because IL-4 is essential during T(H)2 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 T(H)2 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 T(H)2 responses.

Methods: Monocyte-derived DCs (moDCs) conditioned by IL-4 during their differentiation (IL-4-conditioned moDCs [IL-4-moDCs]) were analyzed for T(H)1-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 T(H)1-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 T(H)2-related genes as eosinophil-associated ribonucleases, eosinophil/basophil chemokines, and M2 genes. IL-4 licensed moDCs for the induction of T(H)2 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 T(H)2 responses by blocking T(H)1-polarizing/inflammatory cytokine production through histone hypoacetylation and upregulating T(H)2-related genes.

Keywords: AAMΦ; Alternatively activated macrophage; BMDC; BMMΦ; Bone marrow macrophage; Bone marrow–derived dendritic cell; C-moDC; C-moMΦ; CTL; Caudal mediastinal lymph node; ChIP; Chromatin immunoprecipitation; Control moDC; Control moMΦ; Conventional dendritic cell; Cytotoxic T lymphocyte; DC; Dendritic cell; Ear; Eosinophil-associated ribonuclease; HDAC; HDM; Histone deacetylase; House dust mite; IL-4; IL-4–DC; IL-4–conditioned DC; IL-4–conditioned moDC; IL-4–conditioned moMΦ; IL-4–moDC; IL-4–moMΦ; Inducible nitric oxide synthase; Monocyte-derived DC; Monocyte-derived macrophage; NO; Nitric oxide; PPARγ; Peroxisome proliferator-activated receptor γ; Quantitative PCR; Signal transducer and activator of transcription; Stat; T(H)2 responses; T(H)2-DC; T(H)2-polarizing DC; TLR; TSA; Toll-like receptor; Trichostatin A; cDC; cM-LN; dendritic cells; house dust mite–induced allergic reactions; iNOS; moDC; moMΦ; monocyte-derived dendritic cells; qPCR.