title: Differential regulation of human eosinophil IL-3, IL-5, and GM-CSF receptor alpha-chain expression by cytokines: IL-3, IL-5, and GM-CSF down-regulate IL-5 receptor alpha expression with loss of IL-5 responsiveness, but up-regulate IL-3 receptor alpha expression.
abstract: Our recent data suggested that tissue eosinophils may be relatively insensitive to anti-IL-5 treatment. We examined cross-regulation and functional consequences of modulation of eosinophil cytokine receptor expression by IL-3, IL-5 GM-CSF, and eotaxin. Incubation of eosinophils with IL-3, IL-5, or GM-CSF led to reduced expression of IL-5R alpha, which was sustained for up to 5 days. Eosinophils incubated with IL-5 or IL-3 showed diminished respiratory burst and mitogen-activated protein kinase kinase phosphorylation in response to further IL-5 stimulation. In contrast to these findings, eosinophil expression of IL-3R alpha was increased by IL-3, IL-5, and GM-CSF, whereas GM-CSF receptor alpha was down-regulated by GM-CSF, but was not affected by IL-3 or IL-5. CCR3 expression was down-regulated by IL-3 and was transiently reduced by IL-5 and GM-CSF, but rapidly returned toward baseline. Eotaxin had no effect on receptor expression for IL-3, IL-5, or GM-CSF. Up-regulation of IL-3R alpha by cytokines was prevented by a phosphoinositol 3-kinase inhibitor, whereas this and other signaling inhibitors had no effect on IL-5R alpha down-regulation. These data suggest dynamic and differential regulation of eosinophil receptors for IL-3, IL-5, and GM-CSF by the cytokine ligands. Since these cytokines are thought to be involved in eosinophil development and mobilization from the bone marrow and are present at sites of allergic inflammation, tissue eosinophils may have reduced IL-5R expression and responsiveness, and this may explain the disappointing effect of anti-IL-5 therapy in reducing airway eosinophilia in asthma.
authors.affiliation: Department of Allergy and Clinical Immunology, National Heart and Lung Institute Division, Faculty of Medicine, Imperial College, London, United Kingdom.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gregory
authors.forename: Antje
authors.initials: A
authors.lastname: Kirchem
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
authors.forename: Phillipe
authors.initials: P
authors.lastname: Gevaert
authors.forename: Carol
authors.initials: C
authors.lastname: Pridgeon
authors.forename: Sara M
authors.initials: SM
authors.lastname: Rankin
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Robinson
mesh_terms: D002454:Cell Differentiation / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000276:immunology*; D004804:Eosinophils / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D006801:Humans; D007377:Interleukin-3 / Q000502:physiology*; D015848:Interleukin-5 / Q000037:antagonists & inhibitors / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D016185:Receptors, Interleukin-3 / Q000096:biosynthesis*; D053649:Receptors, Interleukin-5; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology*
chemical_list: C515350:CCR3 protein, human; D007377:Interleukin-3; D015848:Interleukin-5; D021122:Protein Subunits; D012333:RNA, Messenger; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D018123:Receptors, Interleukin; D016185:Receptors, Interleukin-3; D053649:Receptors, Interleukin-5; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases