Homeobox Transcription Factor VentX Regulates Differentiation and Maturation of Human Dendritic Cells

Xiaoming Wu,Hong Gao,Ronald Bleday,Zhenglun Zhu

doi:10.1074/jbc.m113.509158

Abstract

Dendritic cells (DCs) are specialized antigen presentation cells that play critical roles in the initiation and regulation of immune responses. The molecular determinants of DC differentiation and maturation are target of extensive investigation. VentX is a human homeobox transcriptional factor that regulates proliferation and differentiation of hematopoietic cells. In the current study, we report that ablation of VentX expression in monocytes significantly impaired their differentiation into DCs. Conversely, overexpression of VentX in monocytic THP1 cells accelerated their differentiation toward DCs. We showed that VentX regulates DC differentiation, in part, through modulating IL6 expression. Clinically, we found that VentX expression was elevated in intestinal lamina propria DCs (LPDCs) of inflamed mucosa from inflammatory bowel disease patients. Knockdown experiments suggested that VentX is essential for the maturation of LPDCs. In addition, corticosteroid treatment markedly decreased VentX expression in LPDCs and enforced expression of VentX counteracted the effects of corticosteroid on DCs maturation. Our data suggest that VentX is a critical transcriptional regulator of DC differentiation and maturation, and a potential target of immune regulation and therapy.

Highlights

The transcriptional regulation of human dendritic cells (DCs) differentiation and maturation remains incompletely understood
VentX Is Required for Human Primary Monocytes to Dendritic Cell Differentiation—Following our recent finding that VentX is expressed in human primary monocytes [17], we examined VentX expression during primary monocytes to dendritic cell differentiation induced by granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4 treatment
We found that VentX expression underwent a marked increase at both mRNA and protein levels during the induced Dendritic cells (DCs) differentiation (Fig. 1A)

Summary

Background

The transcriptional regulation of human dendritic cells (DCs) differentiation and maturation remains incompletely understood. Dendritic cells (DCs) are specialized antigen presentation cells that play critical roles in the initiation and regulation of immune responses. We found that VentX expression was elevated in intestinal lamina propria DCs (LPDCs) of inflamed mucosa from inflammatory bowel disease patients. Previous studies showed that granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL4 drive peripheral blood CD14ϩ monocytes differentiation to CD14ϪCD1aϩ DCs [2, 9]. VentX is a human homologue of the Xenopus homeobox gene Xom of the BMP4 signaling pathway, and has been defined as a novel hematopoietic transcriptional factor controlling proliferation and differentiation of hematopoietic and immune cells [15,16,17]. Our data suggest that VentX is a key regulator of DC differentiation and maturation and may serve as a target of intervention for inflammatory disorders and immune therapy

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION