Variations in Eosinophil Chemokine Responses: An Investigation of CCR1 and CCR3 Function, Expression in Atopy, and Identification of a Functional CCR1 Promoter

We previously showed in a small group of donors that eosinophils from a subgroup of individuals responded equipotently to CC chemokine ligand (CCL)11/eotaxin and CCL3/macrophage-inflammatory protein-1alpha in assays of eosinophil shape change (CCL3/macrophage-inflammatory protein-1alpha-highly respo...

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Veröffentlicht in:The Journal of immunology (1950) 2003-06, Vol.170 (12), p.6190-6201
Hauptverfasser: Phillips, Rhian M, Stubbs, Victoria E. L, Henson, Mandy R, Williams, Timothy J, Pease, James E, Sabroe, Ian
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container_end_page 6201
container_issue 12
container_start_page 6190
container_title The Journal of immunology (1950)
container_volume 170
creator Phillips, Rhian M
Stubbs, Victoria E. L
Henson, Mandy R
Williams, Timothy J
Pease, James E
Sabroe, Ian
description We previously showed in a small group of donors that eosinophils from a subgroup of individuals responded equipotently to CC chemokine ligand (CCL)11/eotaxin and CCL3/macrophage-inflammatory protein-1alpha in assays of eosinophil shape change (CCL3/macrophage-inflammatory protein-1alpha-highly responsive (MHR) donors). In this study, we investigated the functional role of CCL3 in eosinophil responses in 73 donors. MHR donors, identified by their eosinophil shape change responses, represented approximately 19% of the donor pool. Eosinophils from these donors showed increased eosinophil CCR1 expression and also underwent CCL3-mediated chemotaxis and up-regulation of CD11b. All MHR donors gave a history of atopy-associated diseases. In a further study, we prospectively recruited 110 subjects, subdivided into nonatopics or atopics, and investigated expression of CCR1 and CCR3 on eosinophils, basophils, monocytes, and neutrophils. Eosinophil CCR1 expression was non-normally distributed in atopics, although higher CCR1 expression levels were not predictive of a diagnosis of atopy or atopic disease. We identified the CCR1 promoter and investigated its function. We found a minimal promoter within 177 bp of the transcription start site, and an upstream enhancer region that facilitated expression in leukocyte cell lines. Collectively, these data demonstrate that MHR individuals form an important subgroup that, when associated with a diagnosis of allergic disease, may require tailored therapy to modulate eosinophil recruitment. Identification of a functional CCR1 promoter will facilitate the study of possible genetic determinants underlying this potentially important clinical phenotype.
doi_str_mv 10.4049/jimmunol.170.12.6190
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We found a minimal promoter within 177 bp of the transcription start site, and an upstream enhancer region that facilitated expression in leukocyte cell lines. Collectively, these data demonstrate that MHR individuals form an important subgroup that, when associated with a diagnosis of allergic disease, may require tailored therapy to modulate eosinophil recruitment. Identification of a functional CCR1 promoter will facilitate the study of possible genetic determinants underlying this potentially important clinical phenotype.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>12794150</pmid><doi>10.4049/jimmunol.170.12.6190</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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subjects Adolescent
Adult
Animals
Base Sequence
CD11b Antigen - biosynthesis
Cell Line
Cell Size - immunology
Chemokine CCL3
Chemokine CCL4
Chemotactic Factors, Eosinophil - physiology
Chemotaxis, Leukocyte - immunology
Dose-Response Relationship, Immunologic
Eosinophils - cytology
Eosinophils - immunology
Eosinophils - metabolism
HL-60 Cells
Humans
Hypersensitivity, Immediate - immunology
Leukocytes - immunology
Leukocytes - metabolism
Macrophage Inflammatory Proteins - pharmacology
Mice
Middle Aged
Molecular Sequence Data
Promoter Regions, Genetic - immunology
Prospective Studies
Receptors, CCR1
Receptors, CCR3
Receptors, Chemokine - biosynthesis
Receptors, Chemokine - genetics
Receptors, Chemokine - isolation & purification
Receptors, Chemokine - physiology
Transfection
Up-Regulation - immunology
title Variations in Eosinophil Chemokine Responses: An Investigation of CCR1 and CCR3 Function, Expression in Atopy, and Identification of a Functional CCR1 Promoter
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