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

被引：60
作者：
Phillips R.J. [1 ,3 ]
Lutz M. [1 ]
Premack B. [1 ,2 ,4 ]
机构：
[1] Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles
[2] Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles
[3] Department of Discovery Research, Intermune, Brisbane, CA 94005
[4] Department of Technology Development, ChemoCentryx Inc., San Carlos, CA
来源：
Journal of Inflammation | / 2卷 / 1期
关键词：
Human; Cellular Differentiation; Cell Surface Molecules; Gene Regulation;
D O I：
10.1186/1476-9255-2-14
中图分类号：
学科分类号：
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. © 2005 Phillips et al; licensee BioMed Central Ltd.
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