title: IL-16 activates plasminogen-plasmin system and promotes human eosinophil migration into extracellular matrix via CCR3-chemokine-mediated signaling and by modulating CD4 eosinophil expression.
abstract: Increased eosinophil counts are a major feature of asthmatic airways. Eosinophil recruitment requires migration through epithelium and tissue extracellular matrix by activation of proteases. We assessed the capacity of IL-16, a CD4(+) cell chemotactic factor, to induce migration of eosinophils through a reconstituted basement membrane and evaluated the proteases, mediators, and receptors involved in this migration. IL-16 added to lower chambers of Invasion Chambers elicited eosinophil migration through Matrigel. This effect was decreased by inhibition of the plasminogen-plasmin system (Abs against urokinase plasminogen activator receptor or plasminogen depletion), but not by anti-matrix metalloproteinase-9 Abs. Abs against CD4 also inhibited IL-16-induced eosinophil migration. At the baseline level, few eosinophils (4.6% positive cells with a mean fluorescence of 0.9) expressed surface membrane CD4, while most permeabilized eosinophils (68% positive cells with a mean fluorescence of 18) express the CD4 Ag. TNF-pretreatment increased surface membrane CD4(+) expression by 6-fold as previously described, and increased IL-16-induced cell migration by 2.2-fold. Incubation of eosinophils with IL-16 also increased surface membrane CD4 expression by 5.4-fold, supporting the role of CD4 as receptor for IL-16. Abs against CCR3, eotaxin, or RANTES blocked IL-16-induced migration. In conclusion, IL-16 promotes eosinophil migration in vitro, by activating the plasminogen-plasmin system and increasing the membrane expression of its receptor. This effect is initiated via CD4 and mediated via the release of CCR3 ligand chemokines. Interestingly, most eosinophils express intracellular CD4. Hence, IL-16 may play an important role in the recruitment of blood eosinophils to the bronchial mucosa of asthmatics.
authors.affiliation: Unité de Recherche en Pneumologie, Centre de Recherche de l'Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval, Sainte-Foy, Québec, Canada.
authors.forename: Claudine
authors.initials: C
authors.lastname: Ferland
authors.forename: Nicolas
authors.initials: N
authors.lastname: Flamand
authors.forename: Francis
authors.initials: F
authors.lastname: Davoine
authors.forename: Jamila
authors.initials: J
authors.lastname: Chakir
authors.forename: Michel
authors.initials: M
authors.lastname: Laviolette
mesh_terms: D000328:Adult; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000502:physiology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D054413:Chemokine CCL11; D018946:Chemokine CCL5 / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism; D002631:Chemotactic Factors, Eosinophil / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D003094:Collagen / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D004338:Drug Combinations; D004804:Eosinophils / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology / Q000276:immunology; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism / Q000502:physiology; D006801:Humans; D019410:Interleukin-16 / Q000502:physiology*; D007797:Laminin / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D008297:Male; D010958:Plasminogen / Q000378:metabolism / Q000502:physiology; D010960:Plasminogen Activators / Q000502:physiology*; D011509:Proteoglycans / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: C515456:CCL11 protein, human; C515350:CCR3 protein, human; D015704:CD4 Antigens; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D004338:Drug Combinations; D019410:Interleukin-16; D007797:Laminin; D011509:Proteoglycans; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; C059485:matrigel; D010958:Plasminogen; D003094:Collagen; D010960:Plasminogen Activators; D005341:Fibrinolysin