Differential signaling mechanisms regulate expression of CC chemokine receptor-2 during monocyte maturation

Journal of Inflammation

Brett Premack³  Marin Lutz¹  Roderick J Phillips² 

[1]Department of Physiology David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California, 90095 USA

[2]Department of Discovery Research, Intermune, 3280 Bayshore Blvd, Brisbane, California, 94005 USA

[3]Department of Technology Development, ChemoCentryx Inc., 1539 Industrial Road, San Carlos, California USA

关键词: Gene Regulation;    Cell Surface Molecules;    Cellular Differentiation;    Human;   

Others  :  826683
DOI  :  10.1186/1476-9255-2-14

 received in 2004-12-15, accepted in 2005-10-31,  发布年份 2005

【 摘 要 】

Background

Peripheral blood monocytes and monocyte-derived macrophages are key regulatory components in many chronic inflammatory pathologies of the vasculature including the formation of atherosclerotic lesions. However, the molecular and biochemical events underlying monocyte maturation are not fully understood.

Methods

We have used freshly isolated human monocytes and the model human monocyte cell line, THP-1, to investigate changes in the expression of a panel of monocyte and macrophage markers during monocyte differentiation. We have examined these changes by RT-PCR and FACS analysis. Furthermore, we cloned the CCR2 promoter and analyzed specific changes in transcriptional activation of CCR2 during monocyte maturation.

Results

The CC chemokine receptor 2 (CCR2) is rapidly downregulated as monocytes move down the macrophage differentiation pathway while other related chemokine receptors are not. Using a variety of biochemical and transcriptional analyses in the human THP-1 monocyte model system, we show that both monocytes and THP-1 cells express high levels of CCR2, whereas THP-1 derived macrophages fail to express detectable CCR2 mRNA or protein. We further demonstrate that multiple signaling pathways activated by IFN-γ and M-CSF, or by protein kinase C and cytoplasmic calcium can mediate the downregulation of CCR2 but not CCR1.

Conclusion

During monocyte-to-macrophage differentiation CCR2, but not CCR1, is downregulated and this regulation occurs at the level of transcription through upstream 5' regulatory elements.

【 授权许可】

   
2005 Phillips et al; licensee BioMed Central Ltd.

【 图 表 】

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