title: Variations in eosinophil chemokine responses: an investigation of CCR1 and CCR3 function, expression in atopy, and identification of a functional CCR1 promoter.
abstract: 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.
authors.affiliation: Leukocyte Biology Section, Division of Biomedical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Rhian M
authors.initials: RM
authors.lastname: Phillips
authors.forename: Victoria E L
authors.initials: VE
authors.lastname: Stubbs
authors.forename: Mandy R
authors.initials: MR
authors.lastname: Henson
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Williams
authors.forename: James E
authors.initials: JE
authors.lastname: Pease
authors.forename: Ian
authors.initials: I
authors.lastname: Sabroe
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D039481:CD11b Antigen / Q000096:biosynthesis; D002460:Cell Line; D048429:Cell Size / Q000276:immunology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002631:Chemotactic Factors, Eosinophil / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004804:Eosinophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000276:immunology*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011446:Prospective Studies; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification* / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation / Q000276:immunology
chemical_list: C515300:CCR1 protein, human; C515350:CCR3 protein, human; D039481:CD11b Antigen; C515301:Ccr1 protein, mouse; C515351:Ccr3 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002631:Chemotactic Factors, Eosinophil; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine