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Expression of syndecan, a putative low affinity fibroblast growth factor receptor, in the early mouse embryo.

Syndecan is an integral membrane proteoglycan that binds cells to several interstitial extracellular matrix components and binds to basic fibroblast-growth factor (bFGF) thus promoting bFGF association with its high-affinity receptor. We find that syndecan expression undergoes striking spatial and temporal changes during the period from the early cleavage through the late gastrula stages in the mouse embryo. Syndecan is detected initially at the 4-cell stage. Between the 4-cell and late morula stages, syndecan is present intracellularly and on the external surfaces of the blastomeres but is absent from regions of cell-cell contact. At the blastocyst stage, syndecan is first detected at cell-cell boundaries throughout the embryo and then, at the time of endoderm segregation, becomes restricted to the first site of matrix accumulation within the embryo, the interface between the primitive ectoderm and primitive endoderm. During gastrulation, syndecan is distributed uniformly on the basolateral cell surfaces of the embryonic ectoderm and definitive embryonic endoderm, but is expressed with an anteroposterior asymmetry on the surface of embryonic mesoderm cells, suggesting that it contributes to the process of mesoderm specification. In the extraembryonic region, syndecan is not detectable on most cells of the central core of the ectoplacental cone, but is strongly expressed by cells undergoing trophoblast giant cell differentiation and remains prominent on differentiated giant cells, suggesting a role in placental development. Immunoprecipitation studies indicate that the size of the syndecan core protein, although larger than that found in adult tissues (75 versus 69 x 10(3) Mr), does not change during peri-implantation development. The size distribution of the intact proteoglycan does change, however, indicating developmental alterations in its glycosaminoglycan composition. These results indicate potential roles for syndecan in epithelial organization of the embryonic ectoderm, in differential axial patterning of the embryonic mesoderm and in trophoblast giant cell function.

Animals↗

Sandwich immunoassay for the measurement of murine syndecan-4.

A sensitive and specific immunoassay for mouse syndecan-4 is described. The assay is a non-competitive direct sandwich enzyme-linked immunosorbent assay based on the production of an affinity-purified polyclonal antibody directed against syndecan-4 extracellular domain, used both as a trapping and detecting antibody. The standard curve is constructed with recombinant 6-His-tagged syndecan-4 extracellular domain. The assay allowed quantification of syndecan-4 core protein in the partially purified proteoglycan fraction from adipocyte 3T3-F442A cells, as well as in the cellular whole and clarified lysates. Removal of glycosaminoglycan chains on syndecan-4 core protein is required for maximal epitope exposure. The standard curve ranged between 7 and 70 fmol per well. For the 14 standard curves run on different days, the absorbance at 490 nm for 35.5 fmol of recombinant syndecan-4 was 0.610 +/- 0.110 (n = 14) with a corresponding blank absorbance of 0.089 +/- 0.030. At low (5.7 fmol) and high (42.8 fmol) levels of whole cell syndecan-4, the intra-assay and inter-assay coefficients of variation were 4.9 and 15.3 percent, and 3.3 and 9.7 percent, respectively. A survey of the syndecan-4 expression in various mouse tissues shows that syndecan-4 is highly expressed in the kidney, brain, testes and liver, but can also be measured in several different adipose tissue sites.

3T3 Cells↗

Heparan sulfate-mediated cell aggregation. Syndecans-1 and -4 mediate intercellular adhesion following their transfection into human B lymphoid cells.

Because syndecans are present at sites of cell-cell contact in vivo it has been hypothesized that they play a role in mediating cell-cell adhesion. However, there has been no direct evidence to support this notion. To address this question, B lymphoid (ARH-77) cells were transfected with the cDNA for murine syndecan-1. Unlike the parental cells, the transfectants form large multicellular aggregates in suspension cultures and stain intensely for syndecan-1 at sites of cell-cell contact. Using rotation-mediated aggregation assays, we find that aggregation of syndecan-1-transfected cells is dependent on divalent cations and is inhibited by the following: (i) addition of heparin and heparin-like glycosaminoglycans, (ii) removal of heparan sulfate from the cell surface, or (iii) addition of exogenous purified syndecan-1. Mixing of syndecan-1-transfected and control-transfected cells results in aggregates containing both cell types indicating that aggregation occurs through a heterophilic adhesion mechanism in which heparan sulfate chains bind to a counter-receptor present on these cells. Importantly, syndecan-4-transfected cells also aggregate in a heparan sulfate-dependent manner, while in contrast, betaglycan-transfected cells aggregate poorly. Thus, syndecans may be important mediators of cell-cell adhesion, but this function may not be common to all transmembrane heparan sulfate-bearing proteoglycans.

Animals↗

Differential expression and distribution of syndecan-1 and -2 in the developing periodontium of the rat.

Cell surface proteoglycans are known to interact with adhesion molecules, growth factors and a variety of other effector molecules implying their central role in various aspects of cell-cell and cell-matrix interactions. To investigate the expression and distribution of the cell surface proteoglycans syndecan-1 and -2, the developing periodontal tissues of 3-, 5-, and 8-wk-old male Lewis rats, were stained by specific monoclonal antibodies against syndecan-1, or -2 core protein, using immunohistochemical techniques. The results demonstrated that syndecan-1 and -2 were expressed and distributed differentially in several compartments of the developing periodontal tissues at different ages. Expression of syndecan-1 was noted in areas of intense cellular activity such as the developing apical root tip of the tooth and at the crestal bone where new bone formation was taking place. In contrast, syndecan-2 expression and distribution did not exhibit the same patterns as syndecan-1. Syndecan-2 showed significant differences of distribution in hard tissues undergoing maturation at different ages. These findings indicate that syndecan-1 and -2 may have distinctive functions during morphogenesis, organogenesis and differentiation of the periodontium.

Animals↗

Reduction of syndecan-1 mRNA in cervical-carcinoma cells is involved with the 3' untranslated region.

Syndecan-1 is a transmembrane proteoglycan expressed predominantly in epithelial cells. Studies with immunohistochemistry have shown that syndecan-1 expression is reduced in carcinoma derived from human epidermis. Here we show that syndecan-1 mRNA, which is abundant in human primary keratinocyte (HK) and HaCaT spontaneous immortalized keratinocyte, is decreased in cervical-carcinoma cell lines. Further, in relation to a long and well-conserved 3' untranslated region (3' UTR) of syndecan-1 cDNA, we examined whether 3' UTR is involved with syndecan-1-mRNA reduction in cervical-carcinoma cells. A stable transfection experiment showed that addition of the 3' UTR does not affect expression in HaCaT, but that syndecan-1 cDNA containing the 3' UTR is not expressed efficiently selectively in cervical-carcinoma cell lines. The transient assay with CAT reporter plasmids linking the 3' UTR confirmed this, and indicated that the 3' end of the 3' UTR (nt 2285-2410) is required to influence expression in cervical-carcinoma cells. Further excessive expression of syndecan-1 suppressed growth in cervical-carcinoma cells. These results demonstrate that the reduction of syndecan-1 mRNA involved with the 3' untranslated region gives growth advantage to cervical-carcinoma cells.

Amino Acid Sequence↗

Increased syndecan expression by pleiotrophin and FGF receptor-expressing astrocytes in injured brain tissue.

Syndecan-1, -2, -3, and -4 are heparan sulfate proteoglycans that are differentially expressed during development and wound repair. To determine whether syndecans are also involved in brain injury, we examined the expression of syndecan core proteins genes in cryo-injured mouse brain, using in situ hybridization. All syndecan mRNA transcripts were similarly expressed in the region surrounding the necrotic tissue, exhibiting peak levels at day 7 after injury. Comparison with cellular markers showed that reactive astrocytes were the primary source of syndecans. Syndecans serve as co-receptors for fibroblast growth factor (FGF) and as a reservoir for another heparin-binding growth factor, pleiotrophin (PTN, or heparin-binding growth-associated molecule. In our model, FGF receptor1 (FGFR1) and PTN mRNA levels were upregulated in reactive astrocytes. The distribution patterns of FGFR1 and PTN overlapped considerably with those of syndecan-1 and -3 mRNAs, respectively. These results suggest that syndecans are expressed primarily in reactive astrocytes, and may provide a supportive environment for regenerating axons in concert with heparin-binding growth factors (e.g., FGF and PTN) in the injured brain.

Animals↗

Syndecan-1 signals independently of beta1 integrins during Raji cell spreading.

Syndecan-1-expressing Raji lymphoid cells (Raji-S1 cells) bind and spread rapidly when attaching to matrix ligands that contain heparan sulfate-binding domains. However, these ligands also contain binding sites for integrins, which are widely known to signal, raising the question of whether the proteoglycan core protein participates in generation of the signal for spreading. To address this question, the spreading of the Raji-S1 cells is examined on ligands specific for either beta1 integrins, known to be present on the Raji cells, or the syndecan-1 core protein. The cells adhere and spread on invasin, a ligand that activates beta1 integrins, the IIICS fragment of fibronectin, which is a specific ligand for the alpha4beta1 integrin, or mAb281.2, an antibody specific for the syndecan-1 core protein. The signaling resulting from adhesion to the syndecan-specific antibody appears integrin independent as (i) the morphology of the cells spreading on the antibody is distinct from spreading initiated by the integrins alone; (ii) spreading on the syndecan or integrin ligands is affected differently by the kinase inhibitors tyrphostin 25, genistein, and staurosporine; and (iii) spreading on the syndecan-specific antibody is not disrupted by blocking beta1 integrin activation with mAb13, a beta1 inhibitory antibody. These data demonstrate that ligation of syndecan-1 initiates intracellular signaling and suggest that this signaling occurs when cells expressing syndecan-1 adhere to matrix ligands containing heparan sulfate-binding domains.

Antibodies, Monoclonal↗

Synergistic effect of tumor necrosis factor-alpha and interferon-gamma on enterocyte shedding of syndecan-1 and associated decreases in internalization of Listeria monocytogenes and Staphylococcus aureus.

Syndecan-1 is a heparan sulfate proteoglycan expressed on epithelia, and its ectodomain can be shed into the extracellular milieu, affecting a variety of cellular functions. Using two bacteria known to react with heparan sulfate, Listeria monocytogenes and Staphylococcus aureus, experiments were designed to clarify the effect of syndecan-1 shedding on bacterial internalization by human HT-29 enterocytes. Mature enterocytes were incubated with tumor necrosis factor (TNF)-alpha and/or interferon (IFN)-gamma for 16h prior to addition of bacteria. These cytokines acted synergistically to decrease syndecan-1 expression, assessed by visual observations of syndecan-1 expression on enterocytes using immunohistochemistry and a monoclonal antibody to the syndecan-1 core protein, by quantifying this fluorescent intensity, and by quantifying the concentration of shed syndecan-1 using an enzyme-linked immunoabsorbent assay. Neither IFN-gamma nor TNF-alpha alone had a noticeable effect on L. monocytogenes internalization, but a mixture of both cytokines resulted in decreased (P<0.01) internalization. Enterocyte preincubation with TNF-alpha alone, and with both cytokines, was associated with decreased S. aureus internalization, at P<0.05 and P<0.01, respectively. Thus, TNF-alpha and IFN-gamma acted synergistically to shed syndecan-1 ectodomains from HT-29 enterocytes, and shedding was associated with decreased internalization of two pathogenic bacteria, suggesting that syndecan-1 shedding may modulate the pathogenesis of specific microbes.

Enterocytes↗

Syndecan-1 expression in locally invasive and metastatic prostate cancer.

OBJECTIVES: To determine the significance of syndecan-1 expression, a cell-surface heparan sulfate proteoglycan in localized and metastatic prostate cancer. METHODS: We performed a retrospective analysis of 76 men with Gleason sum 6 or 7 prostate cancer treated by radical prostatectomy and a separate cohort of 75 men with metastatic prostate cancer. Syndecan-1 immunoreactivity was measured in primary prostate specimens or in samples from metastatic sites and correlated with patient outcome. RESULTS: Syndecan-1 was expressed in normal basal and secretory epithelial cells, 26% of radical prostatectomy specimens, and 35% of metastatic disease. No association was found between syndecan-1 positivity and prostate-specific antigen recurrence in the collective cohort of Gleason sum 6 and 7 cancers. However, when stratified by Gleason sum, syndecan-1 immunoreactivity (immunoreactivity score 150 or greater) was associated with a greater recurrence rate in Gleason sum 7 cancers. Expression of syndecan-1 was significantly greater in soft tissue than in bone metastasis (P = 0.048, Fisher's exact test). CONCLUSIONS: Consistent with a possible biochemical role for syndecan-1 in prostate cancer progression and metastasis, syndecan-1 expression correlated with serologic recurrence in Gleason sum 7 prostate cancer and was highly expressed in soft-tissue metastases.

Adenocarcinoma↗

Expression of syndecan-1 is common in human lung cancers independent of expression of epidermal growth factor receptor.

In order to determine syndecan-1 expression in lung cancer, we examined 115 lung cancer specimens and 17 lung cancer cell lines. Syndecan-1 was immunohistochemically stained with a polyclonal antibody in 115 paraffin-embedded specimens; 84 cases out of 97 non-small cell lung cancer (NSCLC) and eight cases out of 18 small cell lung cancer (SCLC) were positively stained. Simultaneously, epidermal growth-factor receptor (EGFR) was stained; 47 cases out of 97 NSCLC and one case of 18 SCLC were positively stained. No significant correlation was shown between EGFR and syndecan-1 expression (P=0.68). Syndecan-1 mRNA was detectable in 16 of 17 lung cancer cell lines and EGFR mRNA in nine of 17. Eight cell lines had syndecan-1 mRNA as well as EGFR mRNA. PR-39 (1 microM) and 80 pM transforming growth factor-beta(1) (TGF-beta(1)), did not increase expressions of syndecan-1 mRNA and EGFR in five lung cancer cell lines. We concluded that lung cancer had detectable syndecan-1; however, expression of syndecan-1 protein did not correlate with survival time of lung cancer patients.

Aged↗

Pretreatment serum syndecan-1 levels and outcome in small cell lung cancer patients treated with platinum-based chemotherapy.

Syndecan-1 is a multifunctional transmembrane heparan sulphate proteoglycan (HSPG) that is present on a variety of cell types. The extracellular syndecan domains can be shed from the cell surface in a highly regulated process called ectodomain shedding. We studied the influence of soluble syndecan-1 on outcome in 88 small cell lung cancer (SCLC) patients treated within the context of two randomised clinical trials with platinum-based therapy. Serum syndecan-1 concentrations were determined using enzyme-linked immunosorbent assay (ELISA) from sera taken prior to initiation of chemotherapy. Patients with the serum syndecan-1 level within the highest tertile (>212 microg/l) had only 38% 1-year and 3% 2-year survival, whereas 58% of those with a lower serum level survived for 1 year and 25% for 2 years following the diagnosis (P=0.0034). A high serum syndecan-1 level (>212 microg/l) was associated with a high pretreatment lactate dehydrogenase (LDH) level (P=0.0024) and a poor Karnofsky's performance status (P=0.021), but not with the clinical stage or the presence of distant metastases at diagnosis. A high serum syndecan-1 level had independent influence on survival also in a multivariate analysis (the relative risk, RR, 1.68; 95% CI, 1.02-2.77; P=0.044) together with the clinical stage (RR, 1.72; 95% CI, 1.05-2.82; P=0.032). We conclude that high pretreatment serum syndecan-1 level is associated with poor prognosis in SCLC treated with platinum-based chemotherapy.

Adult↗

The myeloma cell antigen syndecan-1 is lost by apoptotic myeloma cells.

Syndecan-1 is a cell membrane proteoglycan that binds extracellular matrix components and various growth factors. It is expressed only on malignant plasma cells in bone marrow samples from patients with multiple myeloma (MM). Several reports have suggested that syndecan-1 was present only on a part of the myeloma cells. By using either IL-6-dependent myeloma cell lines or primary myeloma cells stained by annexin V, we report here that syndecan-1 was rapidly lost by myeloma cells undergoing apoptosis. In the same experimental conditions, expression of other cell membrane antigens such as CD38, HLA class-I or CD49d on apoptotic myeloma cells was not affected. In addition, we show that syndecan-1 loss was independent of activation of the gp130 IL-6 transducer. Dexamethasone induced a strong apoptosis of myeloma cells associated with the loss of syndecan-1. Finally, by using freshly-explanted tumoural samples, we show that syndecan-1 rapidly disappeared from myeloma cells in association with induction of apoptosis. In conclusion we showed that syndecan-1 is a marker for viable myeloma cells which is rapidly lost by apoptotic cells. These results emphasize the usefulness of anti-syndecan-1 antibodies to purge tumoural cells from haemopoietic grafts or to purify these cells for further manipulations for immuno or gene therapies.

ADP-ribosyl Cyclase↗

Multiple heparan sulfate chains are required for optimal syndecan-1 function.

Syndecans have three highly conserved sites available for heparan sulfate attachment. To determine if all three sites are required for normal function, a series of mutated syndecans having two, one, or no heparan sulfate chains were expressed in ARH-77 cells. Previously, we demonstrated that expression of wild-type syndecan-1 on these myeloma cells mediates cell-matrix and cell-cell adhesion and inhibits cell invasion into collagen gels. Here we show that to optimally mediate each of these activities, all three sites of heparan sulfate attachment are required. Generally, an increasing loss of syndecan-1 function occurs as the number of heparan sulfate attachment sites decreases. This loss of function is not the result of a decrease in either the total amount of cell surface heparan sulfate or syndecan-1 core protein. In regard to cell invasion, cells expressing syndecan-1 bearing a single heparan sulfate attachment site exhibit a hierarchy of function based upon the position of the site within the core protein; the presence of an available attachment site at serine 47 confers the greatest level of activity, while serine 37 contributes little to syndecan-1 function. However, when all three heparan sulfate chains are present, significantly greater biological activity is observed than is predicted by the sum of the activities occurring when the chains act individually. This synergy provides a functional basis for the evolutionary conservation of the three heparan sulfate attachment sites on syndecans and supports the idea that molecular heterogeneity, which is characteristic of proteoglycans, contributes to their functional diversity.

Cell Adhesion↗

Syndecan-1 expression inhibits myoblast differentiation through a basic fibroblast growth factor-dependent mechanism.

Expression of syndecan-1, a cell-surface heparan sulfate proteoglycan, is down-regulated during skeletal muscle differentiation (Larraín, J., Cizmeci-Smith, G., Troncoso, V., Stahl, R. C., Carey, D. J., and Brandan, E. (1997) J. Biol. Chem. 272, 18418-18424). We examined the role of syndecan-1 in basic fibroblast growth factor (bFGF)-dependent inhibition of myogenesis. C2C12 myoblasts were stably transfected with an expression plasmid containing the rat syndecan-1 coding region cDNA. Constitutive syndecan-1 expression resulted in a strongly diminished capacity of the transfected clones to differentiate and to express skeletal muscle-specific markers such as fusion, creatine kinase, and myosin. The expression of myogenin, a master transcription factor for muscle differentiation, was also reduced and delayed. Analysis of the induction of a myogenin promoter-driven reporter revealed that syndecan-1 expression resulted in a 6-7-fold increase in sensitivity to bFGF-dependent inhibition of myogenin expression. Transfecting the cells with a plasmid containing myogenin cDNA reversed the inhibition of myogenin transcriptional activation and myosin expression in syndecan-1-transfected cells; however, cell fusion was not observed. These results demonstrate that syndecan-1 expression enhances cell responsiveness to bFGF and inhibits myoblast fusion and suggest that muscle terminal differentiation is regulated by syndecan-1 expression.

Animals↗

Heparan sulfate regulates targeting of syndecan-1 to a functional domain on the cell surface.

In polarized B lymphoid cells, syndecan-1 is targeted specifically to a discrete membrane domain termed the uropod that is located at the cell's trailing edge. Within this functional domain, syndecan-1 promotes cell-cell adhesion and concentration of heparin binding growth factors. The present study reveals the surprising finding that targeting of syndecan-1 to uropods is mediated by its heparan sulfate chains and that targeting is regulated by cell surface events rather than solely by intracellular mechanisms. The addition of exogenous heparin or the treatment of polarized cells with heparitinase initiates a rapid and dramatic redistribution of uropod syndecan-1 over the entire cell surface, and a mutated syndecan-1 lacking heparan sulfate chains fails to concentrate within uropods. Interestingly, the heparan sulfate-bearing proteoglycans glypican-1 and beta glycan fail to concentrate in uropods, indicating that targeting may require heparan sulfate structural motifs unique to syndecan-1 or that the core protein of syndecan-1 participates in specific interactions that promote heparan sulfate-mediated targeting. These findings suggest functional specificity for syndecan-1 within uropods and, in addition, reveal a novel mechanism for the targeting of molecules to discrete membrane subcellular domains via heparan sulfate.

Animals↗

Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion.

Heparanase (HPSE-1) is involved in the degradation of both cell-surface and extracellular matrix (ECM) heparan sulfate (HS) in normal and neoplastic tissues. Degradation of heparan sulfate proteoglycans (HSPG) in mammalian cells is dependent upon the enzymatic activity of HPSE-1, an endo-beta-d-glucuronidase, which cleaves HS using a specific endoglycosidic hydrolysis rather than an eliminase type of action. Elevated HPSE-1 levels are associated with metastatic cancers, directly implicating HPSE-1 in tumor progression. The mechanism of HPSE-1 action to promote tumor progression may involve multiple substrates because HS is present on both cell-surface and ECM proteoglycans. However, the specific targets of HPSE-1 action are not known. Of particular interest is the relationship between HPSE-1 and HSPG, known for their involvement in tumor progression. Syndecan-1, an HSPG, is ubiquitously expressed at the cell surface, and its role in cancer progression may depend upon its degradation. Conversely, another HSPG, perlecan, is an important component of basement membranes and ECM, which can promote invasive behavior. Down-regulation of perlecan expression suppresses the invasive behavior of neoplastic cells in vitro and inhibits tumor growth and angiogenesis in vivo. In this work we demonstrate the following. 1) HPSE-1 cleaves HS present on the cell surface of metastatic melanoma cells. 2) HPSE-1 specifically degrades HS chains of purified syndecan-1 or perlecan HS. 3) Syndecan-1 does not directly inhibit HPSE-1 enzymatic activity. 4) The presence of exogenous syndecan-1 inhibits HPSE-1-mediated invasive behavior of melanoma cells by in vitro chemoinvasion assays. 5) Inhibition of HPSE-1-induced invasion requires syndecan-1 HS chains. These results demonstrate that cell-surface syndecan-1 and ECM perlecan are degradative targets of HPSE-1, and syndecan-1 regulates HPSE-1 biological activity. This suggest that expression of syndecan-1 on the melanoma cell surface and its degradation by HPSE-1 are important determinants in the control of tumor cell invasion and metastasis.

Adenocarcinoma↗

Syndecan-1 mediates cell spreading in transfected human lymphoblastoid (Raji) cells.

Syndecan-1 is a cell surface proteoglycan containing a highly conserved transmembrane and cytoplasmic domain, and an extracellular domain bearing heparan sulfate glycosaminoglycans. Through these domains, syndecan-1 is proposed to have roles in growth factor action, extracellular matrix adhesion, and cytoskeletal organization that controls cell morphology. To study the role of syndecan-1 in cell adhesion and cytoskeleton reorganization, mouse syndecan-1 cDNA was transfected into human Raji cells, a lymphoblastoid cell line that grows as suspended cells and exhibits little or no endogenous cell surface heparan sulfate. High expressing transfectants (Raji-Sl cells) bind to and spread on immobilized thrombospondin or fibronectin, which are ligands for the heparan sulfate chains of the proteoglycan. This binding and spreading as not dependent on the cytoplasmic domain of the core protein, is mutants expressing core proteins with cytoplasmic deletions maintain the ability to spread. The spreading is mediated through engagement of the syndecan-1 core protein, as the Raji-S 1 cells also bind to and spread on immobilized mAb 281.2, an antibody specific for the ectodomain of the syndecan-1 core protein. Spreading on the antibody is independent of the heparan sulfate glycosaminoglycan chains and can be inhibited by competition with soluble mAb 281.2. The spreading can be inhibited by treatment with cytochalasin D or colchicine. These data suggest that the core protein of syndecan-1 mediates spreading through the formation of a multimolecular signaling complex at the cell surface that signals cytoskeleton reorganization. This complex may form via intramembrane or extracellular interactions with the syndecan core protein.

Animals↗

Ability of the heparan sulfate proteoglycan syndecan-1 to participate in bacterial translocation across the intestinal epithelial barrier.

Although hundreds of microbial species reside in the human intestinal tract, comparatively few (e.g., Escherichia coli and other enterobacteria, Enterococcus faecalis, etc.) are typically associated with systemic infection in postsurgical, shock, and trauma patients. Syndecan-1 is the predominant cell surface heparan sulfate proteoglycan expressed on epithelia, and there is substantial evidence that heparan sulfate participates in interactions of a variety of frankly pathogenic microbes with mammalian cells. To investigate the role of syndecan-1 in interactions of enteric flora with intestinal epithelium, bacteria that might use the enterocyte as a portal of entry for systemic infection (including E. faecalis, E. coli, and other enterobacteria, and several species of staphylococci and streptococci) were studied for their abilities to interact with syndecan-1. Streptococcus bovis, S. agalactiae, S. pyogenes, Staphylococcus aureus, and S. epidermidis showed increased adherence to ARH-77 cells transfected to express syndecan-1. Heparin, a heparan sulfate analog, inhibited internalization of S. bovis, S. agalactiae, S. pyogenes, and S. aureus by HT-29 enterocytes (prominent syndecan-1 expression), but not Caco-2 enterocytes (relatively low syndecan-1 expression). Data from experiments with Chinese hamster ovary cells with altered glycosaminoglycan expression indicated that heparan sulfate and chondroitin sulfate (glycosaminoglycans on the syndecan-1 ectodomain) participated in bacterial interactions with mammalian cells. Thus, although E. faecalis, E. coli, and other gram-negative enterobacteria did not appear to interact with syndecan-1, this heparan sulfate proteoglycan may mediate enterocyte interactions with some staphylococci and streptococci that are known to cause systemic infections in specific populations of high-risk, immunosuppressed, postsurgical, and trauma patients.

Animals↗