title: Transcriptome of hypoxic immature dendritic cells: modulation of chemokine/receptor expression.
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.
authors.affiliation: Laboratory of Molecular Biology, Giannina Gaslini Institute, Genoa, Italy. annamariaricciardi@ospedale-gaslini.ge.it
authors.forename: Annamaria
authors.initials: A
authors.lastname: Ricciardi
authors.forename: Angela Rita
authors.initials: AR
authors.lastname: Elia
authors.forename: Paola
authors.initials: P
authors.lastname: Cappello
authors.forename: Maura
authors.initials: M
authors.lastname: Puppo
authors.forename: Cristina
authors.initials: C
authors.lastname: Vanni
authors.forename: Paolo
authors.initials: P
authors.lastname: Fardin
authors.forename: Alessandra
authors.initials: A
authors.lastname: Eva
authors.forename: David
authors.initials: D
authors.lastname: Munroe
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wu
authors.forename: Mirella
authors.initials: M
authors.lastname: Giovarelli
authors.forename: Luigi
authors.initials: L
authors.lastname: Varesio
mesh_terms: D015687:Cell Hypoxia; D002465:Cell Movement; D018925:Chemokines / Q000235:genetics*; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D019707:Receptors, Chemokine / Q000235:genetics*; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018925:Chemokines; D019707:Receptors, Chemokine