Expression chemokines and G protein-coupled receptors in myeloid cells

Skelton, Lisa (2003). Expression chemokines and G protein-coupled receptors in myeloid cells. PhD thesis The Open University.



The myeloid cell lineage represents a diverse collection of cell types arising from a common progenitor. Two extreme phenotypes of this lineage belong to the osteoclast and the dendritic cell. This thesis evaluates differential expression of a discrete selection of genes in these two cell types, as they differentiate from their monocyte precursor, utilising well-characterized in vitro differentiation systems and microarray gene technology.

A custom made microarray, including all known chemokine and chemokine receptor genes and related G protein-coupled seven transmembrane (7TM) receptors and ligands, was employed. Expression of transcripts encoding chemokine and chemokine receptors by dendritic cells, and a study of protein expression / production by these cells, served as validation for the microarray gene technology used. In particular, the array data revealed two interesting findings, which were investigated further.

GPR105 gene expression by immature DCs was confirmed by Northern blot analysis. UDP-glucose, an agonist for GPR105, induced calcium responses uniquely in immature DCs, correlating with the gene expression data. This response demonstrated partial sensitivity to pertussis toxin, implicating a 7TM receptor linked to a Gia containing G protein, such as GPR105. Moreover, immature DCs from some donors treated with UDP-glucose exhibited an increase in expression of the co-stimulatory molecule CD86, which correlated with the intensity of an UDP-glucose-induced calcium flux, suggesting a role for this GPCR and its agonist in DC activation.

Production of the angiogenic chemokine CXCL5 by in vitro-derived osteoclast cultures was confirmed by ELISA and attributed to multinuclear cells by immunocytochemistry. Supernatants from osteoclast cultures induced chemotaxis of neutrophils, which was decreased in the presence of an antibody to CXCL5. A role for osteoclast produced CXCL5 in angiogenesis is discussed.

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