Transcriptome of hypoxic immature dendritic cells: Modulation of chemokine/receptor expression

Annamaria Ricciardi, Angela Rita Elia, Paola Cappello, Maura Puppo, Cristina Vanni, Paolo Fardin, Alessandra Eva, David Munroe, Xiaolin Wu, Mirella Giovarelli, Luigi Varesio

Research output: Contribution to journalArticlepeer-review

Abstract

Hypoxia is a condition of low oxygen tension occurring in inflammatory tissues. Dendritic cells (DC) are professional antigen-presenting cells whose differentiation, migration, and activities are intrinsically linked to the microenvironment. DCs will home and migrate through pathologic tissues before reaching their final destination in the lymph node. We studied the differentiation of human monocytes into immature DCs (iDCs) in a hypoxic microenvironment. We generated iDC in vitro under normoxic (iDCs) or hypoxic (Hi-DCs) conditions and examined the hypoxia-responsive element in the promoter, gene expression, and biochemical KEGG pathways. Hi-DCs had an interesting phenotype represented by up-regulation of genes associated with cell movement/migration. In addition, the Hi-DC cytokine/receptor pathway showed a dichotomy between down-regulated chemokines and up-regulated chemokine receptor mRNA expression. We showed that CCR3, CX3CR1, and CCR2 are hypoxia-inducible genes and that CCL18, CCL23, CCL26, CCL24, and CCL14 are inhibited by hypoxia. A strong chemotactic response to CCR2 and CXCR4 agonists distinguished Hi-DCs from iDCs at a functional level. The hypoxic microenvironment promotes the differentiation of Hi-DCs, which differs from iDCs for gene expression profile and function. The most prominent characteristic of Hi-DCs is the expression of a mobility/migratory rather than inflammatory phenotype. We speculate that Hi-DCs have the tendency to leave the hypoxic tissue and follow the chemokine gradient toward normoxic areas where they can mature and contribute to the inflammatory process.

Original languageEnglish
Pages (from-to)175-185
Number of pages11
JournalMolecular Cancer Research
Volume6
Issue number2
DOIs
Publication statusPublished - Feb 1 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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