Plasminogen activator inhibitor-1 supports IL-8-mediated neutrophil transendothelial migration by inhibition of the constitutive shedding of endothelial IL-8/heparan sulfate/syndecan-1 complexes

Lindsay J. Marshall, Lara S.P. Ramdin, Teresa Brooks, Peter Charlton, Janis K. Shute

Research output: Contribution to journalArticle

Abstract

The endothelium is the primary barrier to leukocyte recruitment at sites of inflammation. Neutrophil recruitment is directed by transendothelial gradients of IL-8 that, in vivo, are bound to the endothelial cell surface. We have investigated the identity and function of the binding site(s) in an in vitro model of neutrophil transendothelial migration. In endothelial culture supernatants, IL-8 was detected in a trimolecular complex with heparan sulfate and syndecan-1. Constitutive shedding of IL-8 in this form was increased in the presence of a neutralizing Ab to plasminogen activator inhibitor-1 (PAI-1), indicating a role for endothelial plasminogen activator in the shedding of IL-8. Increased shedding of IL-8/heparan sulfate/syndecan-1 complexes was accompanied by inhibition of neutrophil transendothelial migration, and aprotinin, a potent plasmin inhibitor, reversed this inhibition. Platelets, added as an exogenous source of PAI-1, had no effect on shedding of the complexes or neutrophil migration. Our results indicate that IL-8 is immobilized on the endothelial cell surface through binding to syndecan-1 ectodomains, and that plasmin, generated by endothelial plasminogen activator, induces the shedding of this form of IL-8. PAI-1 appears to stabilize the chemoattractant form of IL-8 at the cell surface and may represent a therapeutic target for novel anti-inflammatory strategies.
Original languageEnglish
Pages (from-to)2057-2065
Number of pages9
JournalJournal of Immunology
Volume171
Issue number4
DOIs
Publication statusPublished - 15 Aug 2003

Keywords

  • monoclonal antibodies
  • blood platelets
  • cell line
  • cell migration inhibition
  • cell-free system
  • leukocyte chemotaxis
  • coculture techniques
  • vascular endothelium
  • fFibrinolysin
  • heparan sulfate proteoglycans
  • heparitin sulfate
  • humans
  • interleukin-8
  • macromolecular substances
  • membrane glycoproteins
  • neutrophils
  • plasminogen activator inhibitor 1
  • proteoglycans
  • recombinant proteins
  • solubility
  • syndecan-1
  • syndecans

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