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Syndecans in inflammation

Protogeneia, Inc., Münster, Germany

¹Correspondence: Protogenia Research Laboratories, Protogeneia, Inc., Mendelstr. 11, D-48149 Münster, Germany. E-mail: protogenia{at}technologiehof-ms.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION THE SYNDECAN FAMILY OF... AN INTRODUCTION TO HEPARAN... CELL SURFACE HEPARAN SULFATE... HEPARAN SULFATE, CYTOKINES, AND... HEPARAN SULFATE, HEPARIN, AND... HEPARAN SULFATE, CHEMOTAXIS, AND... SYNDECAN-1 IN LEUKOCYTE... SYNDECAN-1 IN INFLAMMATORY... SYNDECAN-1 AND SYNDECAN-4 IN... SYNDECAN-4 AS A MODULATOR... SYNDECANS AS RECEPTORS FOR... SYNDECANS AS ORGANIZERS OF... SYNDECAN-2 IN INFLAMMATION A ROLE FOR SYNDECAN-3... SYNDECANS, SHEDDING, AND WOUND... CONCLUDING REMARKS REFERENCES

 
Cell surface heparan sulfate (HS) influences a multitude of molecules, cell types, and processes relevant to inflammation. HS binds to cell surface and matrix proteins, cytokines, and chemokines. These interactions modulate inflammatory cell maturation and activation, leukocyte rolling, and tight adhesion to endothelium, as well as extravasation and chemotaxis. The syndecan family of transmembrane proteoglycans is the major source of cell surface HS on all cell types. Recent in vitro and in vivo data suggest the involvement of syndecans in the modulation of leukocyte–endothelial interactions and extravasation, the formation of chemokine and kininogen gradients, participation in chemokine and growth factor signaling, as well as repair processes. Thus, the complex role of HS in inflammation is reflected by multiple functions of its physiological carriers, the syndecans. Individual and common functions of the four mammalian syndecan family members can be distinguished. Recently generated transgenic and knockout mouse models will facilitate analysis of the individual processes that each syndecan is involved in.

Key Words: cell surface heparan sulfate • leukocyte endothelial interaction • growth factor • chemokine • cytokine

	INTRODUCTION

TOP ABSTRACT INTRODUCTION THE SYNDECAN FAMILY OF... AN INTRODUCTION TO HEPARAN... CELL SURFACE HEPARAN SULFATE... HEPARAN SULFATE, CYTOKINES, AND... HEPARAN SULFATE, HEPARIN, AND... HEPARAN SULFATE, CHEMOTAXIS, AND... SYNDECAN-1 IN LEUKOCYTE... SYNDECAN-1 IN INFLAMMATORY... SYNDECAN-1 AND SYNDECAN-4 IN... SYNDECAN-4 AS A MODULATOR... SYNDECANS AS RECEPTORS FOR... SYNDECANS AS ORGANIZERS OF... SYNDECAN-2 IN INFLAMMATION A ROLE FOR SYNDECAN-3... SYNDECANS, SHEDDING, AND WOUND... CONCLUDING REMARKS REFERENCES

 
INFLAMMATION IS A HIGHLY complex reaction in the vascularized connective tissue to exogenous or endogenous stimuli that can potentially cause cell injury. At the cellular level, interactions between leukocytes and endothelial cells play a key role in acute inflammation, ultimately leading to accumulation of fluid and leukocytes in the extravascular tissue, neutralization of the injurious agent, and repair of injured tissue (1 , 2) (Fig. 1 ; see Table 1 ). In a process known as rolling, proteins of the selectin family initiate the attachment of polymorphonuclear neutrophils (PMNs) and platelets to cytokine-activated endothelium (20 , 21) . Whereas the early phase of rolling in postcapillary venules adjacent to the infected tissue is mediated by endothelial P-selectin and its mucin-like ligand PSGL-1, later phases depend on L-selectin, which is expressed by most circulating leukocytes (22) . Endothelial expression of E-selectin is induced after several hours of endothelial cell activation by interleukin-1 (IL-1), endotoxin, or tumor necrosis factor- (TNF-) and results in slow leukocyte rolling (23) . After rolling, leukocytes undergo a rapid activation step that activates integrin function and allows for arrest and firm adhesion to the endothelium (24) . Activated integrins (LFA-1, Mac-1, VLA-4, LPAM-1) interact with members of the immunoglobulin family of adhesion proteins (ICAM-1, ICAM-2, VCAM-1, MAdCAM-1) to mediate firm adhesion. This process also involves chemokines that can mediate rapid clustering of integrins (25 , 26) . The chemokine superfamily of low molecular weight chemotactic cytokines binds to and signals through seven-transmembrane G-protein-linked receptors expressed on leukocytes and other cell types (27 28 29 30) . Chemokines are key mediators in leukocyte extravasation and migration into the infected area, processes that follow physical attachment to the endothelium. Adhesion to extracellular cell matrix (ECM) glycoproteins and secretion of degradative enzymes are pivotal to these processes and regulated by combinatorial signals between ECM, cytokines and chemokines (31) . Shear forces promote leukocyte transmigration across the vascular endothelium (32 33 34) . In the inflamed tissue, neutrophils mobilize a vast array of effector proteins from internal compartments. Reactive oxygen species (ROS) serve to activate neutrophils and fight phagocytosed pathogens (35 36 37) . ROS-mediated neutrophil apoptosis has been implicated in neutrophil deactivation and resolution of inflammation (38) . Repair processes follow to restore tissue integrity and function. The heparin-related glycosaminoglycan (GAG) heparan sulfate (HS) binds to and modifies the function of several molecules involved in the inflammatory process under physiological conditions (see Table 1 ). At the cell surface, proteoglycans (PG) of the syndecan family are the major source of HS (39 , 40) . These highly conserved type I transmembrane HSPGs are expressed in a developmental and cell type-specific pattern and participate in diverse biological processes ranging from morphogenesis to energy metabolism (40) . Recent in vitro experiments and studies using novel knockout mouse models have provided new insights in the role of the syndecans in inflammation. As can be expected from the diversity of HS functions in the inflammatory process, syndecans affect the functional properties of chemokines, leukocytes, and endothelial cells in multiple ways.

View larger version (39K): [in this window] [in a new window]   Figure 1. Actions of heparan sulfate in the multistep model of leukocyte–endothelial interactions (center; see text). A) Cell surface HS (blue) promotes leukocyte recruitment by establishing chemokine (green) gradients at the cell surface (3 4 5 6 7 8) . B) HS interacts with L- and P-selectins (brown) and modulates leukocyte rolling (9 , 10) . C) Integrin (turquoise) activation depends on chemokine (green) action which is modulated by HS (blue). HS facilitates chemokine dimerization (11) . HS induces expression of and binds to attachment molecules (e.g., ICAM-1, purple) on target cells (12 , 13) . D) Leukocyte diapedesis is promoted by HS involved in chemokine gradient formation and regulation of vascular permeability. Heparin binding protein (green oval) interacts with all syndecans and glypican (14) , whereas kininogen (brown oval) binds to syndecan-1, -2, -4, and glypican (15) . HS-degrading enzymes (scissors symbol) are required for extravasation (16) . E) Leukocyte migration and chemotaxis are influenced by HS modulation of chemokine action. Degradation of syndecan-1 HS by platelet heparanase creates HS fragments that markedly activate FGF-2 mitogenicity (17) . HS activates macrophages, which express syndecan-2 capable of presenting FGF-2 (yellow oval) in a form that trans-activates target cells (12 , 18) . Perlecan HS inhibits monocyte binding to subendothelial matrix (19) .

	THE SYNDECAN FAMILY OF CELL SURFACE HEPARAN SULFATE PROTEOGLYCANS

TOP ABSTRACT INTRODUCTION THE SYNDECAN FAMILY OF... AN INTRODUCTION TO HEPARAN... CELL SURFACE HEPARAN SULFATE... HEPARAN SULFATE, CYTOKINES, AND... HEPARAN SULFATE, HEPARIN, AND... HEPARAN SULFATE, CHEMOTAXIS, AND... SYNDECAN-1 IN LEUKOCYTE... SYNDECAN-1 IN INFLAMMATORY... SYNDECAN-1 AND SYNDECAN-4 IN... SYNDECAN-4 AS A MODULATOR... SYNDECANS AS RECEPTORS FOR... SYNDECANS AS ORGANIZERS OF... SYNDECAN-2 IN INFLAMMATION A ROLE FOR SYNDECAN-3... SYNDECANS, SHEDDING, AND WOUND... CONCLUDING REMARKS REFERENCES

 
The syndecans are a family of highly conserved type I transmembrane heparan sulfate proteoglycans that are expressed in a developmental and cell type-specific pattern (39 40 41) . The amino-terminal signal sequence of the core protein is followed by an ectodomain containing Ser-Gly consensus sequences for glycosaminoglycan attachment, a single highly conserved transmembrane domain and a short highly conserved cytoplasmic domain (Fig. 2 ). All syndecan proteins carry HS chains, and some core proteins can be additionally substituted with chondroitin sulfate (CS) chains (40 , 44) . Although the implications of this observation are unclear at present, one has to keep in mind that some of the GAG-dependent inflammation-related functions of the respective syndecans could be mediated by CS. Four members of the syndecan family have been cloned in mammals. In the adult, syndecan-1 is expressed on epithelial cells and malignant plasma cells, syndecan-2 is present on endothelial cells and fibroblasts, syndecan-3 is predominantly found in the nervous system, whereas syndecan-4 is more ubiquitously expressed (39 , 40) . During development, tissue-specific expression of the different syndecans varies in a regulated manner, with syndecan-1 expression starting as early as cell stage 4 of embryonic development (39 , 41) . The major functional domain of the syndecans, the HS chains, bind specifically to a large number of extracellular ligands, which are active in processes as diverse as morphogenesis, tissue repair, host defense, tumor development, and energy metabolism (40 , 45 46 47) . Syndecans play a major role as matrix and cell surface receptors, coreceptors for growth factor signaling, internalization receptors and soluble paracrine effectors. The GAG composition of syndecans can vary extensively. For example, there are significant differences in the disaccharide composition and the size and frequency of iduronate-rich highly sulfated regions of the HS chains of syndecan-1 from fibroblastic, endothelioid and epithelial cells. Furthermore, the number and size of the GAG chains can vary in a tissue- and cell type-specific manner (reviewed in ref 39 ). These differences are reflected by a change in ligand binding properties and thus a change in syndecan function. For example, syndecan-1 from tooth mesenchyme can bind the ECM protein tenascin, whereas syndecan-1 from mammary epithelial cells cannot (48) .

View larger version (49K): [in this window] [in a new window]   Figure 2. Domain structure of syndecans. Syndecans are characterized by highly conserved transmembrane and cytoplasmic domains. The cytoplasmic domains can be phosphorylated and contain two constant regions (C1, C2) which are separated by a variable region (V). These regions are known to bind a variety of intracellular ligands, including kinases and structural proteins (39 , 40) . The intact ectodomains of the syndecans can be cleaved at a site close to the plasma membrane (juxtamembrane domain JMD), thus forming a soluble effector molecule (40 , 42) . A cell binding domain (CBD) of the extracellular domain has been described for syndecan-4 (43) . The heparan sulfate chains of the syndecans are attached to conserved GAG-attachment sites at the distal end of the ectodomains. Syndecans are shown in dimeric form.

A variety of molecules interacting with the highly conserved cytoplasmic domains of several syndecans have recently been identified: syntenin, CASK, synectin and synbindin bind to the carboxyl-terminal EFYA motif present in all syndecans, whereas syndesmos binds to the membrane proximal and variable regions (Fig. 2) (49 50 51 52 53) . Whereas the role for syndecans as coreceptors in growth factor signaling is well established, recent research has shown that at least syndecan-4 and syndecan-1 appear to be capable of independent signaling (40 , 54 55 56 57) . As coreceptors, syndecans increase the local concentrations of growth factors and promote receptor dimerization (40) . The cytoplasmic tail syndecan-4 binds to phosphatidylinositol 4,5-bisphosphate (PIP2) and activates protein kinase C (PKC) . Hepatocyte growth factor (HGF) binding to syndecan-1 promotes activation of PI3-kinase and MAPK pathways (58) . Soluble syndecan-1 appears to act as a carrier for HGF in vivo and it has been implicated in playing a role in the pathology of myeloma by modulating cytokine activity within the bone marrow (59) .

Whereas the cytoplasmic domains of the syndecans participate in signaling and interactions with the actin cytoskeleton, most functions of the extracellular domains can be attributed to the HS chains rather than the core protein. This view is supported by studies on the model proteoglycan, minican, a recombinant syndecan-1 with an extensively truncated core protein which still contains its heparan sulfate chains (60) . Apart from binding to ECM proteins and fibroblast growth factors, minican inhibits the proliferation of S115 mouse mammary carcinoma cells, thus acting like a biologically active form of the intact syndecan-1 ectodomain.

Although syndecans are the major physiological form of heparan sulfate at the cell surface, the GPI-anchored glypicans and cell-associated extracellular HSPGs like perlecan can contribute to some of the effects of HS on inflammatory processes (40 , 61 , 62) . Glypican can restore the receptor binding ability of oxidized VEGF165, a mitogen for endothelial cells, thus acting like a chaperone (63) . Although glypican acts as a functional adaptor for other group II subfamily secretory phospholipase A2s, it does not influence sPLA(2)-IIF, which modulates inflammatory reactions through regulation of arachidonic acid metabolism (64) . In an in vitro cell invasion assay, Liu et al. (65) studied the role of syndecans and glypicans expressed by the same cell line. Whereas nontransfected ARH-77 cells did not adhere to collagen I and invaded collagen gels, syndecan-1-, -2-, and -4-expressing cells bound to collagen I and failed to invade collagen gels. Cells transfected with glypican-1 did not bind to collagen and remained invasive. A chimera consisting of the glypican extracellular domain fused to the syndecan transmembrane and cytoplasmic domains, mediated binding to collagen and invasiveness. Thus, syndecans and glypican-1 displayed different functions, even though glypican- and syndecan-expressing cells had similar surface levels of HS and their proteoglycans displayed similar affinities for collagen.

Prior to describing specific functions of syndecans in the inflammatory process, the role of their major functional domains, the heparan sulfate chains, will be discussed. For a discussion of other HSPG families and an in-depth treatise on other syndecan functions, the reader is referred to a number of excellent recent reviews (40 , 61 , 66 67 68) .

	AN INTRODUCTION TO HEPARAN SULFATE

TOP ABSTRACT INTRODUCTION THE SYNDECAN FAMILY OF... AN INTRODUCTION TO HEPARAN... CELL SURFACE HEPARAN SULFATE... HEPARAN SULFATE, CYTOKINES, AND... HEPARAN SULFATE, HEPARIN, AND... HEPARAN SULFATE, CHEMOTAXIS, AND... SYNDECAN-1 IN LEUKOCYTE... SYNDECAN-1 IN INFLAMMATORY... SYNDECAN-1 AND SYNDECAN-4 IN... SYNDECAN-4 AS A MODULATOR... SYNDECANS AS RECEPTORS FOR... SYNDECANS AS ORGANIZERS OF... SYNDECAN-2 IN INFLAMMATION A ROLE FOR SYNDECAN-3... SYNDECANS, SHEDDING, AND WOUND... CONCLUDING REMARKS REFERENCES

 
The basic structure of the highly anionic glycosaminoglycan heparan sulfate consists of alternating N-acetylglucosamine and glucuronic acid residues. A series of enzymatic reactions in the Golgi apparatus results in replacement of acetyl groups with sulfate groups, epimerization of glucuronic acid to iduronic acid, and sulfation of the C-6 and C-3 hydroxyl groups of glucosamine and the C-2 hydroxyl groups of uronic acid residues (69 , 70) . Since these modification reactions do not reach completion, the final HS chain has a multidomain structure (71) . N- and O-sulfate groups clustered in iduronic acid-rich regions alternate with disaccharide repeats containing very little O-sulfate. Between these two domains, regions containing disaccharide repeats which differ in the degree of N-sulfation are found (70 , 71) .

A functional consequence of the molecular diversity within the HS chain is the formation of defined structural motifs which allow for specific binding of ligands. Under physiological conditions, HS and the structurally related, extensively sulfated mast cell GAG heparin bind to and modulate the action of a large number of extracellular ligands (40 , 72) . Heparin is still frequently used in experimental applications for practical reasons and because of its pharmacological importance. However, its structure does not reflect the domain organization of cell surface HS, which is crucial for the ligand binding properties and some of the physiological functions of HS. Therefore, one has to keep in mind that data generated using heparin rather than HS or HS-degrading enzymes might not represent a physiological situation.

The importance of HS and its specific structural properties for several physiological processes has recently been demonstrated in mice being defective in enzymes involved in HS synthesis (73 , 74) . Mouse embryos carrying a homozygous deletion of the gene EXT1, encoding an HS polymerase, lack an organized mesoderm and extraembryonic tissues and die at the gastrulation stage (75) . Targeted disruption in mice of NDST-1, one of four genes encoding N-deacetylase/sulfotransferases involved in introducing the first modifications of the HS chain, resulted in highly reduced N-sulfation of HS in most tissues (76) . The mice die shortly after birth due to lung failure caused by insufficient secretion of surfactant (77) . The targeted inactivation of the functionally related enzyme NDST-2 in mice resulted in a defect in connective tissue-type mast cells, which is characterized by a dramatically decreased number of granules, lack of mast cell proteases and lack of sulfated heparin (78 , 79) . After mast cell activation, neutrophils are recruited into the peritoneum of NST-2 -/- mice. This appears to be due to the presence of TNF- and other cytokines, which can still be stored and secreted upon degranulation. Lack of the enzyme required for 2-O-sulfation of HS results in death in the neonatal period and kidney agenesis (80) . A molecular analysis of HS from these Hs2st-/- mice reveals that although 2-O-sulfation was absent, the domain structure of HS was intact and compensatory increases in N- and 6-O-sulfation maintained overall charge density (74) . Although the affinity of the mutant HS for FGF-1 and FGF-2 were reduced, the signaling response to these growth factors appeared to be normal.

A more detailed analysis of these mouse models will very likely reveal more subtle phenotypes, some of which may be related to inflammation. Currently, mouse models being defective in additional enzymes involved in HS synthesis are being created. This will allow for a better understanding of the in vivo roles of HS in the near future (73) . In the following sections, the interaction of HS and heparin with ligands involved in inflammation and its functional consequences are discussed (see Table 1 , Fig. 1 ).

	CELL SURFACE HEPARAN SULFATE IN LEUKOCYTE DEVELOPMENT AND DENDRITIC CELL ACTIVATION

TOP ABSTRACT INTRODUCTION THE SYNDECAN FAMILY OF... AN INTRODUCTION TO HEPARAN... CELL SURFACE HEPARAN SULFATE... HEPARAN SULFATE, CYTOKINES, AND... HEPARAN SULFATE, HEPARIN, AND... HEPARAN SULFATE, CHEMOTAXIS, AND... SYNDECAN-1 IN LEUKOCYTE... SYNDECAN-1 IN INFLAMMATORY... SYNDECAN-1 AND SYNDECAN-4 IN... SYNDECAN-4 AS A MODULATOR... SYNDECANS AS RECEPTORS FOR... SYNDECANS AS ORGANIZERS OF... SYNDECAN-2 IN INFLAMMATION A ROLE FOR SYNDECAN-3... SYNDECANS, SHEDDING, AND WOUND... CONCLUDING REMARKS REFERENCES

 
An aberrant development and maturation of leukocytes can have a profound influence on leukocyte properties and the inflammation process in the adult organism. An imbalance in the level of cell-surface HS during leukocyte development might be one of the underlying causes for the inflammation-related phenotypes of syndecan-1 and syndecan-4 -/- mice (86 , 87) .

Schofield et al. (88) investigated expression of proteoglycan core proteins in human bone marrow stroma both at the mRNA and protein level. Perlecan, glypican-1, syndecan-4 and a splice variant of syndecan-3 were identified as the major HSPGs which create the correct environment for maintenance and development of hematopoietic stem and progenitor cells. Mac-1 and CD45 mediate the adhesion of hematopoietic progenitor cells to stromal cells via stromal cell HS (89) . Long-term culture-initiating cells of human hematopoietic progenitors can be maintained for 5 wk in the absence of stroma, when O-sulfated-HS GAGs are added to IL-3 and either MIP-1 or PF (83) . HS-PGs purified from granuloma-derived connective tissue are capable of binding to and mediating the growth-promoting activity of granulocyte-macrophage stimulating factor (GM-CSF) and IL-3. They could act as an artificial myelopoietic stroma (90) . As a component of the thymic microenvironment, HS has been shown to play a critical role in the maturation of T cell precursors (91) , and cell-surface HSPGs mediate IL-7-dependent B lymphopoiesis (92) .

The products of activated leukocytes, such as TNF- and IL-1, are capable of activating dendritic cells. In some situations, dendritic cells can be activated in the absence of exogenous stimuli. Heparan sulfate, which is rapidly released under conditions of inflammation and tissue damage, has been shown to induce phenotypic maturation of immature murine dendritic cells (93) . HS-stimulated dendritic cells showed an up-regulation of activation markers, increased allostimulatory capacity and a release of TNF-, IL-1ß, and IL-6.

	HEPARAN SULFATE, CYTOKINES, AND CHEMOKINES

TOP ABSTRACT INTRODUCTION THE SYNDECAN FAMILY OF... AN INTRODUCTION TO HEPARAN... CELL SURFACE HEPARAN SULFATE... HEPARAN SULFATE, CYTOKINES, AND... HEPARAN SULFATE, HEPARIN, AND... HEPARAN SULFATE, CHEMOTAXIS, AND... SYNDECAN-1 IN LEUKOCYTE... SYNDECAN-1 IN INFLAMMATORY... SYNDECAN-1 AND SYNDECAN-4 IN... SYNDECAN-4 AS A MODULATOR... SYNDECANS AS RECEPTORS FOR... SYNDECANS AS ORGANIZERS OF... SYNDECAN-2 IN INFLAMMATION A ROLE FOR SYNDECAN-3... SYNDECANS, SHEDDING, AND WOUND... CONCLUDING REMARKS REFERENCES

 
Cytokines and chemokines are crucial mediators of inflammatory responses, controlling the behavior of a wide range of target cells (27 28 29 30) . HS causes activation of macrophages leading to the production of cytokines and prostaglandin E2 (PGE2). HS-induced production of IL-6 uses activation of a tyrosine kinase and of nuclear factor B (NF-B), whereas production of PGE2 involves the activation of protein kinase C and elevation of intracellular calcium (94) . In peritoneal macrophages, heparan sulfate can up-regulate ICAM-1 and ICAM-1A,and cause the release of IL-1, IL-6, TNF, IL-12, TGF-ß, and PGE2. Cytotoxic capability is induced by HS (12) . Interferon gamma (IFN-) -stimulated peritoneal macrophages show a dramatic increase in cytotoxicity toward L1210 leukemia target cells upon treatment with HS, but not other GAGs, including heparin (12) .

HS binds to and modifies the action of several cytokines and their receptors (see Table 1 ). All chemokines tested so far have positively charged domains and bind to and are functionally modulated by heparin (4 , 29) . HS-bound IL-2 regulates T cell homeostasis (5) , and HS binding of IL-10 and IL-5, respectively, modulates their activity (3 , 6) . Moreover, heparin and HS antagonize binding and activation of a model endothelium by IFN- (7) . It has been suggested that IFN- binds to membrane-associated HS before engagement with the high-affinity receptor followed by signal transduction. RANTES, macrophage inflammatory protein1 (MIP-1) and MIP-1ß are secreted by CD8+ cytotoxic T lymphocytes as a macromolecular complex containing sulfated proteoglycans (8) . HS facilitates RANTES inhibition of HIV-1 infection of monocytes.

Chemokines play critical roles in leukocyte recruitment into sites of inflammation. When immobilized on endothelium, chemokines direct rolling leukocytes to firmly adhere to endothelium. Gradients of both soluble and immobilized chemokines appear to play important roles in leukocyte extravasation into the tissue. HS is known to mediate cell surface oligomerization of chemokines (11) . Patel et al. (95) have shown that under physiological salt concentrations, SLC, TARC, and RANTES bind to mast cells and the ECM (ECM) in rheumatoid arthritis synovium. Binding is inhibited by highly sulfated GAGs and high salt concentrations. Chemokine binding to synovial structures correlated strongly with avidity of chemokine binding to heparin, and a RANTES mutant with decreased heparin avidity was not capable of mast cell or ECM binding.

Heparan sulfate modulates cytolytic T cell responses (96) . Adult T cell leukemia (ATL) cells adhere to endothelial cells through already activated integrins in a process that does not require exogenous stimulation (97) . ATL cell HS can immobilize the T cell integrin trigger MIP-1ß. Competitive interruption of endogenous heparan sulfate proteoglycan synthesis reduces cell surface MIP-1ß and prevents integrin-mediated adhesion to endothelial cells.

The binding of IL-8 to cell surface HSPG is highly important for neutrophil recruitment to an inflammatory site. Heparin and HS enhance neutrophil responses to IL-8 (98) , which can be transported through endothelium in basolateral to luminal polarity in an HS-dependent manner (99) . Goger et al. (100) demonstrated that binding of IL-8 to both heparin and heparan sulfate leads to a structural stabilization, allowing for a prolonged biological effect of the chemokine. Only HS induced structural changes in the dimeric chemokine. This indicates an HS-induced activation of the chemokine with respect to receptor binding.

	HEPARAN SULFATE, HEPARIN, AND LEUKOCYTE–ENDOTHELIAL INTERACTIONS

TOP ABSTRACT INTRODUCTION THE SYNDECAN FAMILY OF... AN INTRODUCTION TO HEPARAN... CELL SURFACE HEPARAN SULFATE... HEPARAN SULFATE, CYTOKINES, AND... HEPARAN SULFATE, HEPARIN, AND... HEPARAN SULFATE, CHEMOTAXIS, AND... SYNDECAN-1 IN LEUKOCYTE... SYNDECAN-1 IN INFLAMMATORY... SYNDECAN-1 AND SYNDECAN-4 IN... SYNDECAN-4 AS A MODULATOR... SYNDECANS AS RECEPTORS FOR... SYNDECANS AS ORGANIZERS OF... SYNDECAN-2 IN INFLAMMATION A ROLE FOR SYNDECAN-3... SYNDECANS, SHEDDING, AND WOUND... CONCLUDING REMARKS REFERENCES

 
Heparan sulfate binds to and modifies the action of several cell surface molecules involved in the interaction of leukocytes with endothelial cells during inflammation. Adherence of leukocytes to endotoxin-stimulated endothelial cells is significantly reduced by heparin-like GAGs in a nonstatic leukocyte–endothelial cell adhesion assay (101) . Selectins play a major role in the inflammatory reaction by initiating neutrophil attachment to activated vascular endothelium. Sulfation is required for selectin-mediated leukocyte–endothelial cell interactions and was recently shown to regulate CD44-mediated leukocyte adhesion to endothelial cells (102) . However, this effect might be due to multiple GAGs, since oversulfated chondroitin/dermatan sulfate can bind to L- and P-selectin and chemokines (103) . Carboxyl-reduced and sulfated heparin exhibits strong anti-P-selectin and anti-L-selectin activity whereas lacking antithrombin-mediated anticoagulant activity (104) . It inhibited P-selectin- and L-selectin-mediated cell adhesion under laminar flow conditions. HS chains enriched in unsubstituted glucosamine units can bind L-selectin and P-selectin, but not E-selectin (9) . Moreover, monocyte attachment to TNF--stimulated aortic endothelium under flow conditions can be significantly inhibited by heparinase treatment, which leads to HS degradation. Heparinase treatment inhibited L-selectin binding to these cells (10) . In an intravital microscopy study, administration of 5000 units/kg of low molecular weight heparin was found to markedly reduce TNF--induced leukocyte rolling, adhesion and tissue infiltration (105) . When heparin was given after TNF-, only leukocyte rolling was reduced whereas firm adhesion of leukocytes was not affected. Although heparin is an adhesive ligand for the leukocyte integrin Mac-1, this interaction by itself appears to be too weak to mediate leukocyte–endothelial cell adhesion under flow conditions (106) . However, heparin inhibits binding of the soluble ligands fibrinogen, factor X and iC3b to Mac-1 (107) . As mentioned earlier, heparin-mediated effects might not necessarily reflect the function of cell surface HS. Therefore, the physiological role of HS in the processes described above remains to be clarified.

Activation of platelets plays an indirect role in mediating leukocyte–endothelial interactions and depends on cell surface HS (108) . The antiangiogenic platelet factor 4 (PF-4) appears to inhibit FGF-2 and VEGF function via competition with heparin/HS binding (84 , 109) .

	HEPARAN SULFATE, CHEMOTAXIS, AND MIGRATION

TOP ABSTRACT INTRODUCTION THE SYNDECAN FAMILY OF... AN INTRODUCTION TO HEPARAN... CELL SURFACE HEPARAN SULFATE... HEPARAN SULFATE, CYTOKINES, AND... HEPARAN SULFATE, HEPARIN, AND... HEPARAN SULFATE, CHEMOTAXIS, AND... SYNDECAN-1 IN LEUKOCYTE... SYNDECAN-1 IN INFLAMMATORY... SYNDECAN-1 AND SYNDECAN-4 IN... SYNDECAN-4 AS A MODULATOR... SYNDECANS AS RECEPTORS FOR... SYNDECANS AS ORGANIZERS OF... SYNDECAN-2 IN INFLAMMATION A ROLE FOR SYNDECAN-3... SYNDECANS, SHEDDING, AND WOUND... CONCLUDING REMARKS REFERENCES

 
Heparan sulfate not only affects leukocyte adhesion to a stimulated endothelium, it also influences leukocyte chemotaxis and transmigration. This effect is either exerted through modulation of chemokine action or through interactions with molecules at the surface of target cells (30) . It has been suggested that cell surface HS may contribute to the integrity of the endothelium through interactions with PECAM-1 (110) .

The interaction between the chemokine MCP-1/CCL-2 and endothelial cell surface GAGs can be antagonized by the addition of heparin (111) . Transendothelial chemotaxis of mononuclear immune cells promoted by MCP-1 could be antagonized almost completely by the addition of heparin. GAG-deficient mutant cells did not support transendothelial migration, suggesting a role of HS and possibly other GAGs in this process. These findings are supported by the observation that carboxyl-reduced and sulfated heparin drastically inhibits neutrophil migration into thioglycollate-inflamed peritoneum of BALB/c mice (104) . Gambero et al. (112) examined the ability of types I, II, and III secretory phospholipases A2 (sPLA2s) to induce human neutrophil chemotaxis. They studied the role of heparan sulfate in this process using HS/heparin and HS-degrading enzymes in the neutrophil chemotaxis assay and found that neutrophil migration in response to sPLA2s involves an interaction of sPLA2s with cell surface heparin/heparan binding sites. This interaction triggered the release of leukotriene B4 and platelet-activating factor.

Neutrophils and monocytes express high amounts of the S100 family proteins MRP-8 and MRP-14. In inflammation, MRP-8/14 heterodimers are deposited onto the endothelium of venules associated with extravasating leukocytes.

In binding studies of MRP-8/14 to the cell surface of an endothelial cell line, Robinson et al. (87) demonstrated that HS and heparin were capable of blocking MRP-14 binding to the endothelial cells and that a GAG-deficient cell line did not support MRP-8/14 binding.

Extravasation and invasion of tissues by leukocytes also depend on the activity of heparanases, endoglycosidases that degrade heparan sulfate proteoglycans (113) . Heparanases can remove all ligand binding sites from HS-PGs either by cleavage of the HS chain from the core protein, or by cleavage of ligand binding motifs in HS. Heparin inhibits heparanase activity of neutrophils, lymphocytes, endothelial cells and platelets, as well as ECM degradation (114) . Extracellular heparanases play roles in remodeling basement membranes at inflammation sites and in tumor cell invasion and metastasis (11 , 115 116 117 118) . They regulate cell growth and differentiation through the release of growth factors that are bound to extracellular and cell surface HS-PGs (17 , 119) .

Obviously, heparan sulfate plays a major role in a multitude of inflammation-related processes. The most abundant form of heparan sulfate at the cell surface is attached to core proteins of the syndecan family (39 , 40) . Upon cleavage from the cell surface, the intact ectodomains of these proteoglycans can also act as soluble effectors. In the following sections, the specific functions of syndecans in the inflammatory process will be discussed (see Table 2 ).

	SYNDECAN-1 IN LEUKOCYTE–ENDOTHELIAL INTERACTIONS

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Although syndecan-1 is primarily known as the epithelial syndecan in adult tissues, it is expressed on leukocytes and endothelial cells, albeit in a regulated manner. The temporally restricted and highly regulated expression is a hallmark of syndecan-1 function both during embryonic development and wound repair (39 , 40 , 120) .

Syndecan-1 is expressed on pre-B cells and plasma cells in their attached states. IL-6, as well as lipopolysaccharide (LPS) stimulation, regulates syndecan-1 expression on B cells (86 , 121) . Syndecan-1 expression has been proposed as a marker for plasma cells in chronic endometritis (122) , and syndecan-1 expression can be induced on macrophages (123 , 124) . In polarized myeloma cells, syndecan-1 is targeted to the uropod, where it promotes cell–cell adhesion and possibly regulates the activity of heparin binding cytokines (125 , 126) . A role for syndecan-1 in lymphoma biology is well established and has recently been reviewed (126) . Syndecan-1 promotes myeloma cell aggregation, acting in concert with the Sp17 protein, which is present on the surface of malignant lymphoid cells, including B- and T-lymphoid cell lines (127) . Heparitinase-treatment abolishes Sp17 binding to myeloma cell surfaces. It is capable of promoting extensive aggregation of cells expressing syndecan-1, but not of cells lacking syndecan-1. Human monocyte-derived macrophages express high levels of syndecans-1, -2, and -4. These syndecans serve as the main attachment receptors for HIV-1 in macrophages (128) , which could explain the inhibitory effect of heparin on HIV-1 infection (8) .

The expression of syndecan-1 can be induced on the surface of endothelial cells on tumor blood vessels (Fig. 3 ), and in the context of wound healing and inflammation (130 , 131) , suggesting a role for syndecan-1 in the interaction of leukocytes with endothelial cells. Increased syndecan-1 expression on endothelial cells is observed in mouse/rat models of myocardial infarction, where infiltrating macrophages account for a substantial increase in syndecan expression (132) . TNF- specifically suppresses syndecan-1 expression at both mRNA and protein levels in a dose-dependent manner on endothelial cells in vivo and in vitro (133) .

View larger version (109K): [in this window] [in a new window]   Figure 3. Induction of syndecan-1 on a Lewis lung carcinoma blood vessel. 1 x 107 cells of a Lewis lung carcinoma were injected into the backs of C57Bl6 mice as described previously (129) . After 10 days, a tumor of 1300 mm3 size was harvested and processed for standard immunohistology on paraffin sections. A) Overlay of differential interference contrast (DIC) and DAPI fluorescence pictures demonstrating the location of the blood vessel. B) Immunostaining with anti-murine syndecan-1 monoclonal antibody 281–2 and a Cy3-labeled goat-anti rat secondary antibody. C) DIC/DAPI staining of control section D) Immunostaining with a rat isotype control IgG antibody, and a Cy3-labeled goat-anti rat secondary antibody. Data by M. Götte and M. Bernfield.

The importance of syndecan-1 in leukocyte–endothelial interactions has recently been uncovered in a study on syndecan-1 knockout (sdc1 -/-) mice (86) . Sdc1 -/- mice develop normally and are fertile (46) , however, when these mice are challenged, highly interesting phenotypes like the resistance to wnt-1-mediated mammary gland tumorigenesis (46) , or resistance to certain microbial lung infections (47) are observed. In a recent study, we demonstrated that lack of syndecan-1 leads to enhanced leukocyte–endothelial cell interactions, increased angiogenesis and increased inflammatory responses (86) . Adhesion of leukocytes to blood vessels in the retinae of sdc1 -/- and +/+ mice was measured in a perfusion-based assay, and a dramatic increase of leukocyte adhesion to the endothelium of sdc1 -/- mice was noted. Surprisingly, bone marrow cross-transplantation experiments between lethally irradiated sdc 1-/- and sdc1 +/+ mice and healthy donor mice suggested that this was largely a leukocyte-mediated effect. Intravital microscopy of mesentery venules was used to distinguish between leukocyte rolling, integrin-mediated adhesion and transmigration. Rolling of leukocytes and platelets upon stimulation with a Ca²⁺-ionophore, which depends on P-selectin and von Willebrandt factor statement on the surface of activated endothelial cells (134 135 136 137) , was found to be normal in sdc1 -/- mice. In contrast, when sdc1 -/- venules were treated with TNF- for 3 h, a dramatic increase of leukocyte adhesion to the vessel wall was observed. This increase was accompanied by a threefold reduction in the number of remaining rolling leukocytes and a reduction of their average velocity. Under the same conditions, sdc1 +/+ mice showed only increased rolling but no pronounced adhesion of leukocytes to the vessel wall. Although previous research had suggested that E-selectin is not involved in HS binding, there is at least one study showing an inhibitory effect of heparin and syndecan-1 on the binding of E-selectin to bovine capillary endothelial cells and human dermal microvascular endothelial cells (81) . E-selectin is expressed by TNF--stimulated endothelium and mediates slow leukocyte rolling, resulting in long transit times of leukocytes through venules (23) .

Whereas the interaction of leukocytes with P-selectin expressed on the activated endothelium did not seem to be involved in the increased leukocyte adhesion seen in sdc1 -/- mice, the slow E-selectin-dependent rolling and the ß-integrin-dependent adhesion process were affected by the absence of syndecan-1. Thus, syndecan-1 acts as a negative modulator of leukocyte–endothelial interactions. The mechanism behind this observation is still under investigation. Lack of syndecan-1 could lead to a dysregulation of chemokine action, or to an exposure of heparin binding sites on molecules involved in the leukocyte–endothelium adhesion process. With respect to leukocyte–endothelial interactions and its functional consequences, syndecan-1 knockout mice appear to be strikingly dissimilar to mouse models of leukocyte adhesion deficiencies (LAD), which carry mutations in adhesion molecules like e.g., selectins or leukocyte integrin subunits (138) . Whereas defects in molecules causing LAD often lead to decreased inflammatory responses, mice lacking the Duffy antigen/receptor for chemokines (DARC) display increased inflammatory reactions after LPS stimulation, and thus show a phenotype more similar to the sdc1 -/- mouse (139) . DARC is expressed on endothelium and erythrocytes, and binds promiscuously to CC and CXC chemokines, like HS (140) . The inflammatory responses in DARC-deficient mice suggests that this molecule could sequester chemokines and prevent them from activating leukocytes (139) . Similar mechanisms might play a role in the inflammatory response of sdc1 -/- mice. Another transgenic mouse model could be of interest with respect to the inflammatory phenotype of sdc1 -/- mice: Increased leukocyte adhesion to endothelium and emigration after stimulation with LPS are seen in a transgenic mouse in which a catalytically inactive form of the cytoplasmic protein tyrosine kinase Fer is expressed (141) . Among other stimuli, growth factor and cytokine responses are transduced via this kinase. Given its role as a coreceptor and possibly an autonomous signaling molecule, it will be worth testing to see if syndecan-1 participates in a pathway involving Fer. At least the cytoplasmic domain of syndecan-3 is capable of binding cytoplasmic tyrosine kinases c-Src and C-Fyn, and phosphorylation of Src is enhanced upon binding of heparin binding-growth associated molecule (HB-GAM) to syndecan-3 (142) . Further experimentation is needed to evaluate if similar mechanisms play a role in the case of syndecan-1 and Fer.

Lack of syndecan-1 appears to promote increased vascular permeability and leukocyte extravasation under inflammatory conditions (86) (M. Götte, unpublished). Enzymatic degradation of HS reduces monocyte binding to the subendothelial matrix (16) and lymphocyte extravasation appears to depend on HS-degrading enzymes which are released by activated platelets, neutrophils and T cells (110 , 143) . Syndecan-1 might be influencing vascular permeability through its interaction with vasoactive kinins (15) and heparin binding protein (HBP) (144) .

In addition to an increased leukocyte–endothelial interaction, increased angiogenesis in a cornea assay was observed in sdc1 -/- mice (86) . Heparin has antiangiogenic properties which are in part due to inhibition of angiogenic chemokines like macrophage-derived IL-8 (29 , 145 , 146) . Neutrophils and macrophages stimulate the proliferation of vascular endothelium, fibroblasts, neural and smooth muscle cells through secretion of heparin binding angiogenic factors such as VEGF and bFGF (147 148 149) . The increased local accumulation of leukocytes seen in sdc1 -/- mice could therefore facilitate angiogenesis (150 , 151) .

	SYNDECAN-1 IN INFLAMMATORY DISEASES OF THE GASTROINTESTINAL TRACT

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In inflammatory bowel disease, the normal healing process during restitution can be disrupted by the inflammation. This may be due to loss of growth factors, cell adhesion molecules, or both, resulting in a reduced rate of healing (152) . Heparin treatment aids healing in ulcerative colitis (152) . Day et al. (153) tested the hypothesis that syndecan-1 as the predominant epithelial syndecan, could contribute to the healing process through its function as a coreceptor for FGF-2. A marked reduction of syndecan-1 immunostaining was found in reparative epithelium from inflammatory bowel disease patients. In vitro experiments demonstrated that gastrointestinal epithelial cells displayed reduced proliferative response to FGF-2 after enzymatic removal of heparan sulfate. The FGF-2 response could be completely restored by the addition of heparin, giving strong support in favor of the postulated function of syndecan-1. Inflammatory bowel disease is also characterized by intestinal permeability changes and large numbers of neutrophils trafficking through the epithelium (154) . Epithelial cells are a source of a number of cytokines and express several cytokine receptors, whereas transepithelial migration of neutrophils can be promoted by chemoattractants such as leukotriene B4, platelet activating factor and N-formyl-peptides (reviewed in ref 154 ). Furuta et al. (155) have suggested that chemokines may associate with epithelial surfaces and activate polymorphonuclear neutrophils (PMN) in hypoxia-induced mucosal disorders. They found that epithelial hypoxia induced surface IL-8 expression and expression of the HSPG perlecan, and possibly other cell-surface HSPGs. Hypoxia-induced IL-8 expression decreased significantly after treatment with heparinase III. Disaccharides derived from heparin and heparan sulfate regulate proinflammatory mediator secretion from intestinal epithelial cells (156) . It is tempting to speculate that the changes in syndecan-1 expression occurring in inflammatory bowel disease might contribute to changes in neutrophil adhesion and transmigration via a modification of chemokine action.

The expression of syndecan-1 in gastric mucosa ulcers was recently studied by in situ hybridization and immunohistochemistry in human stomachs containing an ulcer or early scar tissue (157) . In healthy tissue, syndecan-1 protein was expressed at the basolateral surface of foveolar epithelial cells and the cells of intestinal metaplasia, as well as on the surface of stromal plasma cells. Enhanced staining was seen in elongated regenerative foveolar cells at the healing ulcer margins and in the early scar tissues. Syndecan-1 protein was expressed on the migrating cells on ulcer floors. The authors suggest that syndecan-1 participates in cell adhesion mainly in the foveolar epithelium and plays a role in the healing of gastric ulcers by interacting with heparin binding growth factors. Mice lacking syndecan-1 show delayed skin and corneal wound healing (see discussion below) (40 , 158 , 159) .

	SYNDECAN-1 AND SYNDECAN-4 IN PERIODONTITIS

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The expression of syndecans is differentially regulated at the mRNA level in human periodontal ligament cells (160) : Syndecan-1 expression increases in response to bFGF and PDGF-BB, but drops in response to TGF-ß1, IL-1ß, and IFN-. In contrast, syndecan-2 mRNA levels are up-regulated by TGF-ß1 and IL-1ß stimulation, whereas syndecan-4 expression is not significantly altered by these factors. In gingivitis and chronic periodontitis, syndecan-1 is expressed by lesional B cells/plasma cells, whereas syndecan-4 is expressed by lesional B cells/plasma cells and T cells (161) . Both syndecan-1 and -4 were expressed in the stratified gingival epithelium. The expression of syndecan-1 by peripheral blood cells was found to be decreased in chronic periodontitis subjects, but not in gingivitis subjects. Conversely, Syndecan-1 expression by peripheral blood T cells was increased in gingivitis subjects, but not in periodontitis subjects. The expression of syndecan-1 on peripheral blood monocytes could be modulated by mitogens and growth factors. The authors suggest that T cells may be required to stimulate B cell syndecan-1 expression in chronic periodontitis. Syndecan-4 might facilitate B cell migration or antigen presentation in periodontal disease. In a different study of periodontitis, epithelial loss of syndecan-1 was noted along with a loss of CD44 expression (162) . Expression of syndecan-1 in suprabasal keratinocytes of the epithelium was weak or absent in inflamed tissue, whereas syndecan-1 expression was strong in infiltrating lymphocytes. In addition, expression of the small dermatan sulfate proteoglycans decorin and biglycan was markedly reduced in the periodontal connective tissue in chronic inflammation. Cell surface heparan sulfate efficiently inhibits endocytosis of decorin in a variety of cell types (163) . In summary, syndecan-1/CD 44-dependent adhesion of keratinocytes is decreased and syndecan-1/CD 44-mediated adhesion of lymphocytes is increased in chronic inflammation of the periodontium.

	SYNDECAN-4 AS A MODULATOR OF CYTOKINE AND CHEMOKINE ACTION

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Among the syndecans, syndecan-4 is the ubiquitously expressed member. Therefore, it is no surprise that syndecan-4 is expressed by many cell types relevant to inflammation: Syndecan-4 exists on B lineage lymphocytes (164) , on macrophage-like cells (165) , neutrophils (166) and peripheral blood monocytes (167) . TNF- secreted by hypoxic murine cardiac myocytes can induce syndecan-4 expression on endothelial cells in an NF-B-dependent manner, and by prolonging syndecan-4 mRNA half-life (168) .

Since the cytoplasmic tail of syndecan-4 is capable of binding phosphatidylinositol 4,5-bisphosphate (PIP2) and activating protein kinase C (PKC) , these properties have been suggested to confer signaling functions on syndecan-4 (54 , 56) These signaling functions appear to play a role in the modulation of antithrombin III action on leukocyte chemotaxis by syndecan-4: The serpin antithrombin III (AT III) has anti-inflammatory properties, which are at least in part due to the promotion of endothelial prostacyclin release (169) . In an in vivo endotoxemia model, a reduction of leukocyte adhesion by AT is mediated by prostaglandin (170) . Chemotactic migration of human neutrophils in vitro toward IL-8 or fMet-Leu-Phe is significantly inhibited by AT III (171) , whereas neutrophils migrate toward AT III gradients in the absence of other attractants. The AT III heparin binding site was capable of interacting with neutrophil cell surface HSPGs. AT III-dependent neutrophil-migration could be abolished by pretreating cells with heparinase-1 and anti-syndecan-4 antibodies, suggesting regulation through syndecan-4 (166) . This view is supported by the observation that both syndecan-4 and AT III use similar signaling pathways (171) . Apart from neutrophils, lymphocytes and monocytes from human peripheral blood show chemotaxis toward AT III gradients. Migration of these cells toward IL-8 or RANTES was inhibited by AT III pretreatment (167) . Both effects could be abolished by heparinase-1, chondroitinase, chlorate or anti-syndecan-4 antibody treatment. Since chondroitinase treatment affects chemotaxis too, these effects are not exclusively mediated by the HS chains of syndecan-4. In summary, AT III appears to inhibit chemokine-stimulated migration of neutrophils, monocytes and lymphocytes through syndecan-4 activation of protein kinase C and Rho signaling (55 , 56 , 172) .

A functional link between syndecan-4 and antithrombin-III might be the reason for the degeneration of fetal vessels in the placental labyrinth of syndecan-4 -/- mice (173) . In wild-type mice, syndecan-4 is expressed in these vessels. In syndecan-4 (-/-) embryos at 17.5 gestational days, the area of degenerated fetal vessels in the placental labyrinth is more diffuse and larger than in wild-type controls (173) . Syndecan-4 deficiency impairs the fetal vessels in the placenta, possibly due to a deficit in the anticoagulation mechanism. Mice lacking syndecan-4 are a useful tool in studying the role of syndecan-4 in inflammation. Like syndecan-1 knockout mice, syndecan-4 knockout mice are fertile and develop normally (174) . In wild-type mice, intraperitoneal injection of LPS results in an up-regulation of syndecan-4 in monocytes and microvascular endothelium (87) . In syndecan-4-deficient mice, the LPS-induced up-regulation of the cytokine IL-1ß was not efficiently counteracted by TGFß1. As a result, plasma levels of IL-1ß were higher in the sdc4 -/- mice compared with wild-type mice, resulting in a severe endotoxin shock and high mortality of sdc4 -/- mice (87) . The ubiquitous cytokine TGF-ß lessens the extent of injury to tissues and cells and facilitates their repair (175) . Interestingly, cell surface HS inhibits endocytosis of the dermatan sulfate proteoglycan decorin in aortic endothelial cells (163) . Decorin is an important modulator of TGF-ß function (176 , 177) , and control of the extracellular decorin concentration by cell surface HS might influence TGF-ß-mediated effects in an indirect way.

	SYNDECANS AS RECEPTORS FOR HEPARIN BINDING PROTEIN

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Heparin binding protein (HBP/CAP37) is a proteolytically inactive serin protease homologue that is released from activated neutrophils and that can be induced on endothelial cells by inflammatory mediators (178) . Apart from functions in the recruitment and activation of monocytes and activation of T cells (179 , 180) , HBP plays an important role in PMN-induced increase in vascular permeability and edema formation (144) . Upon neutrophil adhesion to the endothelium, the release of neutrophil-borne HBP is triggered by leukocytic ß2 integrin signaling. HBP induces intracellular gap formation in EC layers in vitro and increased macromolecular efflux in microvessels in vivo, whereas inactivation of HBP prevents neutrophils from inducing endothelial hyperpermeability. By affinity isolation, it has been shown that HBP released from human neutrophils binds to endothelial cell-surface proteoglycans, including all syndecans and glypican (14) . The authors demonstrated that HBP is endocytosed and targeted to mitochondria where it exhibits an antiapoptotic effect, thus prolonging endothelial cell viability. Endocytosis of HBP/CAP37 has been shown to be essential for the enhancement of LPS-induced TNF- production in human monocytes (181) . Syndecans can serve as endocytosis receptors (182 , 183) and cell surface HSPGs have been shown to influence endocytosis of ligands directly and through interactions with their endocytosis receptors (163 , 184) . Although highly suggestive, one can only speculate at present if the increased vascular permeability in TNF--stimulated syndecan-1 knockout mice (86) is due to alterations in HBP function.

	SYNDECANS AS ORGANIZERS OF KININOGEN GRADIENTS

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Kinins are peptide hormones playing a role in the formation of edema, local blood flow regulation, and as mediators of pain sensations. HSPGs appear to play a critical role in recruiting kinin precursors from the plasma and in the assembly of components triggering the release of active kinins from their precursors in proximity to their target cells (15) : Endothelial cell surface digestion with heparinase dramatically reduces kininogen binding capacity. High expression of syndecan-1, syndecan-2, syndecan-4, and glypican in HEK293t cells significantly increased the number of kininogen binding sites. Thus, kininogen binding to cell surface HSPG seems to use mechanisms similar to chemokine immobilization on endothelial cells.

	SYNDECAN-2 IN INFLAMMATION

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In contrast to the syndecan-1 and syndecan-4 knockout mouse models, there are currently no data available on an inflammation-related phenotype of syndecan-2 knockout or transgenic mice. Syndecan-2 expression can be induced by a variety of cytokines, including IL-1, IL-1ß and TGFß (18 , 160 , 185) . Syndecan-2 is involved in the mitogenic activity and signaling of granulocyte-macrophage colony-stimulating factor (GM-CSF) in osteoblasts and appears to act as a coreceptor for this cytokine (186) . Syndecan-2 expression on human macrophages can be induced by LPS and IL-1, resulting in an increased binding of these cells to the macrophage-derived factors FGF-2, VEGF, and hbEGF. Syndecan-2 bound FGF-2 is capable of trans-activating receptor-bearing cells, and it was found to be the major cell-surface HSPG on in vivo activated macrophages in inflammatory synovitis (18) . Along with other members of the syndecan family it may be involved in regulating vascular permeability through the formation of kininogen gradients (see above).

	A ROLE FOR SYNDECAN-3 IN INFLAMMATION?

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Syndecan-3, the predominant syndecan of the nervous system, plays important physiological roles in limb skeletal development (187) , in the control of feeding behavior (45) , and in hippocampal long-term potentiation (188) . Like other members of the syndecan family, it acts as a coreceptor in signaling processes (reviewed in ref 40 ). However, very little is known about its potential role in inflammation. A recently discovered variant of syndecan-3 is expressed in human bone marrow stroma where it might influence maintenance and development of hemopoietic stem and progenitor cells (88) . Consequently, this could have a profound indirect effect on inflammatory responses. Studies on inflammatory responses of syndecan-3 knockout mice (45) should allow for a test of this hypothesis.

	SYNDECANS, SHEDDING, AND WOUND REPAIR: IMPLICATIONS FOR INFLAMMATORY PROCESSES

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Inflammatory processes are closely linked to repair processes, which share the same cell types and molecules (189) . Repair begins during the early phases of inflammation, but is usually completed after the injurious influence is neutralized.

During wound healing, changes in the expression of syndecan-1 and syndecan-4 occur. In chronic venous ulcers, syndecan-4 was found to be predominantly expressed by epidermal basal layer cells in the wound edge, whereas syndecan-1 was expressed in smaller quantities at the epidermal wound margins (190) . During cutaneous wound repair in the mouse, syndecan-1 expression ceases at the surface of epithelial cells migrating into the wound and is induced on the dermal endothelial cells and fibroblasts of the forming granulation tissue (130) . Syndecans-1 and -4 are induced on mesenchymal cells by the antimicrobial peptide PR39, which is present in wound fluids (191) . Within 12 h after incisional injury of murine or neonatal human skin, syndecan-1 and -4 were induced, with syndecan-1 induction taking place primarily on endothelium, whereas syndecan-4 was present throughout the dermis at the site of injury. In contrast, wounded human fetal skin, which heals without a polymorphonuclear cell infiltrate, appreciable fibrosis, or clinically apparent scar, showed no increase in expression of syndecans (131) . Increased syndecan-1 expression in granulation tissue correlates with the hepatic fibrosis induced by the parasitic pathogen Schistosoma mansoni (192) .

The physiological role of syndecan-1 and syndecan-4 in skin wound healing becomes visible in vivo in mice lacking syndecan-1 and syndecan-4, respectively. Syndecan-1 -/- mice show a marked delay in skin and corneal wound healing (40 , 158 , 159) , which is due to delayed formation of cell–cell and cell-matrix contacts of keratinocytes/keratocytes migrating into the wound. Overexpression of syndecan-1 in transgenic mice results in abnormal wound healing, which seems to be due to increased levels of soluble syndecan-1 ectodomain in the wound fluids (40 , 193) . Syndecan-4 -/- mice display statistically significant delays in skin wound healing and impaired angiogenesis in the granulation tissue (194) . Interestingly, transgenic mice that constitutively express the CXC chemokine IP-10 from keratinocytes have an abnormal wound healing response characterized by a more intense inflammatory phase and a prolonged and disorganized granulation phase with impaired blood vessel formation (195) . IP-10 is highly expressed in a number of chronic inflammatory conditions in humans, where it acts as a chemoattractant for activated T cells, and inhibits the proliferation of endothelial cells.

Syndecans maintain the proteolytic balance in wound fluids (196) and the soluble ectodomains appear to be involved in this process. The inflammatory injury regulating wound healing is in part caused by an imbalance between proteases and antiproteases. The activity of these proteases is modified by the heparan sulfate chains of syndecan-1 and syndecan-4, which are shed into acute human dermal wound fluids (197) . In addition, shed syndecan-1 modulates growth factor activity in wound fluids (17) . The low sulfated regions in the HS chains of the syndecan-1 ectodomain inhibit heparin-mediated FGF-2 mitogenicity. Degradation of these regions by platelet heparanase creates HS fragments that markedly activate FGF-2 mitogenicity and are found in wound fluids. Shedding, the regulated proteolytic cleavage of transmembrane proteins near the plasma membrane, results in release of their ectodomains as soluble intercellular regulators (198 199 200) . This process is a means of (co)receptor-down-regulation and converts membrane anchored proteins into soluble effectors, which can compete for ligands with their membrane-anchored counterparts. Shedding of the syndecan-1 ectodomain at a juxtamembrane site occurs constitutively and in a regulated manner (reviewed in ref 40 ). Accelerated shedding of syndecan-1 and syndecan-4 by direct proteolytic cleavage, by cellular stress or other physiologic activators uses distinct intracellular signaling pathways, and seems to involve TIMP-3-sensitive matrix metalloproteinases and non-matrix-type metalloproteinases (42 , 201) .

Apart from a role in wound repair, the shedding of syndecans from the surface of endothelial cells might play a more general role in inflammation: Binding of anti-endothelial cell antibodies and activation of complement on endothelial cells causes the rapid shedding of endothelial cell heparan sulfate proteoglycans of a core protein size similar to syndecan-1 (202 , 203) . The sulfated glycoprotein proteolysis-inducing factor (PIF) induces shedding of syndecans from the surface of HUVEC and liver endothelial cells (204) . In parallel, it induces the proinflammatory cytokines IL-8 and IL-6, and increased expression of the cell surface proteins ICAM-1 and vascular cell adhesion molecule (VCAM). With respect to the inflammation-related phenotypes of the syndecan-1 -/- and syndecan-4 -/- mice one has to keep in mind that increased leukocyte–endothelial interactions (86) and increased sensitivity to LPS (87) might not only be a consequence of the lack of syndecan expression at cell surfaces, but also of soluble syndecans. Being less restricted in their spatial distribution, the soluble ectodomains can interact with a multitude of cell types, as well as soluble and insoluble factors. This expands the repertoire of syndecan functions in inflammation.

	CONCLUDING REMARKS

TOP ABSTRACT INTRODUCTION THE SYNDECAN FAMILY OF... AN INTRODUCTION TO HEPARAN... CELL SURFACE HEPARAN SULFATE... HEPARAN SULFATE, CYTOKINES, AND... HEPARAN SULFATE, HEPARIN, AND... HEPARAN SULFATE, CHEMOTAXIS, AND... SYNDECAN-1 IN LEUKOCYTE... SYNDECAN-1 IN INFLAMMATORY... SYNDECAN-1 AND SYNDECAN-4 IN... SYNDECAN-4 AS A MODULATOR... SYNDECANS AS RECEPTORS FOR... SYNDECANS AS ORGANIZERS OF... SYNDECAN-2 IN INFLAMMATION A ROLE FOR SYNDECAN-3... SYNDECANS, SHEDDING, AND WOUND... CONCLUDING REMARKS REFERENCES

 
Heparin and heparan sulfate influence multiple molecules, cell types, and processes in inflammation (Table 1) . In the past, the multitude of HS-mediated events has often been confusing and hard to analyze. However, an analysis of the proteoglycans which are the physiological carriers of HS chains in multicellular organisms, allows for a more detailed analysis of HS function in inflammation. The syndecans are the major source of cell surface heparan sulfate on all cell types relevant to the inflammatory process. Shedding of their intact ectodomains converts these versatile molecules to soluble effectors which can compete for ligands with their cell-surface counterparts and which can escape the spatial restrictions of membrane-bound molecules. Spatially and temporally regulated expression of syndecan core proteins allows for a control of cell surface HS expression and thus for a regulation of HS-dependent steps during inflammatory events (40) . The differential expression of syndecans in response to inflammatory stimuli is a first sign of their direct involvement in these processes. A plethora of in vitro data on the role of syndecans as coreceptors, signaling receptors and binding partners for chemokines, cytokines, growth factors, integrins and other adhesion molecules, supports their role as integral parts of inflammatory events. It appears that many, if not most, of the HS-mediated effects on inflammation can be replicated by the individual or combined forces of one or several syndecans. Syndecans could therefore serve as new targets for the prevention of pathologic inflammatory events. Recent data on syndecan knockout mouse models provide further evidence for the physiological relevance of syndecan function in vivo. Interference with several steps of HS synthesis (EXT1, NDST-1, Hs2st) results in severe phenotypes in knockout mice (75 76 77 , 80) . However, syndecan-deletions have a more subtle effect which facilitates analysis of their function. Both syndecan-1 and syndecan-4 -/- mice display inflammation-related phenotypes (86 , 87) . A detailed analysis of the mechanistic principles underlying these still complex phenotypes will help to clarify the exact role(s) of the individual members of the syndecan family in the near future.

	ACKNOWLEDGMENTS

 
Original work by Martin Götte and the late Merton Bernfield at Children‘s Hospital (Boston, MA, USA) was financially supported by Deutscher Akademischer Austauschdienst DAAD (M.G.) and National Cancer Institute Grant RO1-CA-28735 (M.B.).

Received for publication August 27, 2002. Accepted for publication December 20, 2002.

	REFERENCES

TOP ABSTRACT INTRODUCTION THE SYNDECAN FAMILY OF... AN INTRODUCTION TO HEPARAN... CELL SURFACE HEPARAN SULFATE... HEPARAN SULFATE, CYTOKINES, AND... HEPARAN SULFATE, HEPARIN, AND... HEPARAN SULFATE, CHEMOTAXIS, AND... SYNDECAN-1 IN LEUKOCYTE... SYNDECAN-1 IN INFLAMMATORY... SYNDECAN-1 AND SYNDECAN-4 IN... SYNDECAN-4 AS A MODULATOR... SYNDECANS AS RECEPTORS FOR... SYNDECANS AS ORGANIZERS OF... SYNDECAN-2 IN INFLAMMATION A ROLE FOR SYNDECAN-3... SYNDECANS, SHEDDING, AND WOUND... CONCLUDING REMARKS REFERENCES

 

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