title: Differential ability of exogenous chemotactic agents to disrupt transendothelial migration of flowing neutrophils.
abstract: Neutrophils migrate through endothelium using an ordered sequence of adhesive interactions and activating signals. To investigate the consequences of disruption of this sequence, we characterized adhesion and migration of neutrophils perfused over HUVEC that had been treated with TNF-alpha for 4 h and evaluated changes caused by exogenously added chemotactic agents. When HUVEC were treated with 2 U/ml TNF, flowing neutrophils adhered, with the majority rolling and relatively few migrating through the monolayer. If fMLP, IL-8, zymosan-activated plasma (a source of activated complement factor C5a), epithelial cell-derived neutrophil-activating peptide (ENA-78), or growth-regulating oncogene, GRO-alpha, was perfused over these neutrophils, they stopped rolling and rapidly migrated over the monolayer, but did not penetrate it. When HUVEC were treated with 100 U/ml TNF, the majority of adherent neutrophils transmigrated. If neutrophils were treated with fMLP, IL-8, C5a, ENA-78, or GRO-alpha just before perfusion over this HUVEC, transmigration, but not adhesion, was abolished. However, when platelet-activating factor was used to activate neutrophils, migration through HUVEC treated with 100 U/ml TNF was not impaired, and migration through HUVEC treated with 2 U/ml TNF was actually increased. Transmigration required ligation of CXC chemokine receptor-2 on neutrophils, and differential desensitization of this receptor (e.g., by fMLP but not platelet-activating factor) may explain the pattern of disruption of migration. Thus, transmigration may require presentation of the correct activators in the correct sequence, and inappropriate activation (e.g., by systemic activators) could cause pathological accumulation of neutrophils in the vessel lumen.
authors.affiliation: Department of Physiology, The Medical School, University of Birmingham, Birmingham, United Kingdom.
authors.forename: N T
authors.initials: NT
authors.lastname: Luu
authors.forename: G E
authors.initials: GE
authors.lastname: Rainger
authors.forename: G B
authors.initials: GB
authors.lastname: Nash
mesh_terms: D002448:Cell Adhesion / Q000276:immunology; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000378:metabolism / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D015936:Complement C5a / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D004730:Endothelium, Vascular / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000378:metabolism / Q000502:physiology; D018123:Receptors, Interleukin / Q000378:metabolism / Q000502:physiology; D023063:Receptors, Interleukin-8B; D014471:Umbilical Veins
chemical_list: C475829:CXCL1 protein, human; C486263:CXCL5 protein, human; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D010972:Platelet Activating Factor; D019707:Receptors, Chemokine; D018123:Receptors, Interleukin; D023063:Receptors, Interleukin-8B; D009240:N-Formylmethionine Leucyl-Phenylalanine; D015936:Complement C5a