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

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.

Syndecan-2 Is Expressed in the Microvasculature of Gliomas and Regulates Angiogenic Processes in Microvascular Endothelial Cells

“…Syndecan-2 may exert its effect via regulation of matrix assembly (e.g. basement membrane laminin) as shown previously (6), generation of a chemotactic gradient in a complex with growth factors (as shown for S1) (34,35), or by protecting pro-angiogenic factors from inactivation. Whatever the mechanism, recombinant soluble S2ED that lacks glycanation is biologically effective and may be a target for novel anti-tumor/anti-angiogenic cancer therapies.…”

Activated Syndecan-1 Shedding Contributes to Mice Colitis Induced by Dextran Sulfate Sodium

“…The semi-quantity (IOD ratio) of IL-1 and IL-10 mRNA expression in mouse colon mucosa on day 7 after DSS ingestion were shown in b and d. Data are expressed as mean ± SEM (* p \ 0.001 in the DSS group vs. control; #p \ 0.05 in heparin?DSS group vs. DSS group, n = 6 independent observations) and IL-10) and thus attenuate colitis, which is supported by our present study. To investigate the role of Sdc1 in colitis, genetic colitis models, like the IL-10 KO mice model, are desperately needed for further research; (3) Heparin in serum may competitively inhibit or imitate the function of Sdc1, thus inhibit leukocyte adhering to endotheliocyte and leukopedesis [26], restrain chemotaxis of leukocyte induced by IL-18 [27], repress the formation of proinflammatory factors [28,29], and reduce the metabolic production of active oxygen [30]; (4) Heparin can promote preparation of epithelial tissue by combining with growth factors [31,32,58]. Using Sdc1 KO mice, recent study showed low molecular weight heparin has protective effect on DSS colitis as a substitute of Sdc1 function [59].…”

“…The exact anti-inflammatory mechanisms of heparin have not yet been found. Because heparin is an analog of Sdc-1, it can competitively inhibit or imitate the function of Sdc-1, thus inhibit leucocyte adhering to endotheliocyte and leukopedesis [26], restrain chemotaxis of leucocyte induced by IL-18 [27], repress the formation of pro-inflammatory factors [28,29], and reduce the metabolic production of active oxygen [30]. In addition, heparin can promote reparation of epithelial tissue by combining with growth factors [31,32].…”

Heparan Sulfate-modulated, Metalloprotease-mediated Sonic Hedgehog Release from Producing Cells

“…Therefore, ShhNp lipidation may also serve as a prerequisite for the formation of oligomeric nanostructures and ultimately HSPG-associated complexes on Bosc23 cells. Because HSPGs can undergo proteolytic shedding together with bound ligands (46), ShhNp⅐HSPG complexes may be shed simultaneously, resulting in the observed labile, high molecular weight structures. This hypothesis is compatible with the described stability of ShhNp multimers in the presence of detergent or 500 mM NaCl (which is insufficient for disruption of ShhN/HS interactions) (Fig.…”