IngentaConnect Differential pattern of CCR1 internalization in human eosinophils...

Abstract:

Background:

Whereas recent studies underlie the fundamental importance of the CC chemokine receptor 3 (CCR3) for the recruitment of eosinophils in allergic diseases, controversial data exist about the relevance of CCR1 on eosinophils. Therefore, the purpose of this study was to investigate the expression and regulation of CCR1 on eosinophils. Methods:

Flow cytometric analysis of whole blood eosinophils and CD16-negative selected eosinophils from healthy nonatopic donors and from patients with atopic disorders was performed and CCR1 receptor internalization and re-expression were studied. Results:

Flow cytometric analysis of whole blood eosinophils revealed that 17.8% of the donors expressed high levels of CCR1 (CCR1^high) and 82.2% low levels of CCR1 (CCR1^low). A significant down-regulation of CCR1 was induced by 24 h preincubation of isolated eosinophils from CCR1^high donors either with IL-3, CC chemokine ligand 3 (CCL3), CCL5, CCL7, or CCL13. Internalization experiments using eosinophils from CCR1^high donors revealed that CCL5 is more effective to induce CCR1 internalization than CCL3. Whereas CCR1 re-expression after stimulation with CCL3 reached prestimulation levels (120 min: 81.3% relative CCR1 surface expression) CCL5 induced a prolonged CCR1 internalization (120 min: 15.7%). Conclusions:

This study demonstrates a distinct pattern of CCR1 internalization and re-expression in human eosinophils between CCL3 and CCL5, as CCL5 induces a prolonged CCR1 internalization and the basic value is not reached after 24 h. Since prolonged receptor internalization plays a central role in chemokine-mediated inhibition of receptor function, CCR1 seems to be an attractive target on human eosinophils for chemokine receptor blockade besides CCR3.

Keywords: CCR1; CCR3; chemokines; cytokines; eosinophils

Document Type: Research article

DOI: 10.1111/j.1398-9995.2005.00893.x

Affiliations: 1: Department of Dermatology and Allergology, Hannover Medical School 2: Department of Pharmacology and Toxicology, Section for Experimental and Clinical Peptide Research, Hannover Medical School 3: IPF PharmaCeuticals GmbH, An-Institut of Hannover Medical School

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Differential pattern of CCR1 internalization in human eosinophils: prolonged internalization by CCL5 in contrast to CCL3