Regulation of platelet heparanase during inflammation: Role of pH and proteinases

Ihrcke, Nathan S.; Parker, William; Reissner, Kathryn J.; Platt, Jeffrey L.

doi:10.1002/(sici)1097-4652(199806)175:3<255::aid-jcp3>3.0.co;2-n

Cited by 75 publications

(56 citation statements)

References 37 publications

(18 reference statements)

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“…Fractions of each enzyme preparation were boiled and tested to have only trace LPS contamination (Ͻ1% of limiting concentration needed to evoke responses) by Limulus amebocyte lysate assay gel clot method (Seikagaku, Falmouth, MA). Human platelet heparanase was purified as previously described (14), then dialyzed into PBS to a final concentration of 3.4 mg/ml and stored at Ϫ80°C until used. Heparanase activity was measured as previously described (14) to be 0.19 g of heparan sulfate released per microgram of heparanase per hour.…”

Section: Enzyme Purificationmentioning

confidence: 99%

“…The studies were conducted in vitro because heparanase is tightly regulated by pH (14) and because complete depolymerization of heparan sulfate abolishes agonist activity (15). To address this question, we added heparanase purified from human platelets (27) to 24-h-old cocultures of PAECs and murine APCs that were TLR4-positive or -negative, and then assayed TNF-␣.…”

Section: Tnf-␣ Secretion In Response To Enzymatic Degradation Of Hepamentioning

confidence: 99%

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Cutting Edge: An Endogenous Pathway to Systemic Inflammatory Response Syndrome (SIRS)-Like Reactions through Toll-Like Receptor 4

Johnson¹,

Brunn²,

Platt

2004

The Journal of Immunology

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222

174

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Systemic inflammatory response syndrome (SIRS) is typically associated with trauma, surgery, or acute pancreatitis. SIRS resembles sepsis, triggered by exogenous macromolecules such as LPS acting on Toll-like receptors. What triggers SIRS in the absence of infection, however, is unknown. In this study, we report that a SIRS-like response can be induced in mice by administration of soluble heparan sulfate, a glycosaminoglycan associated with nucleated cells and extracellular matrices, and by elastase, which cleaves and releases heparan sulfate proteoglycans. The ability of heparan sulfate and elastase to induce SIRS depends on functional Toll-like receptor 4, because mutant mice lacking that receptor or its function do not respond. These results provide a molecular explanation for the initiation of SIRS.

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Section: Enzyme Purificationmentioning

confidence: 99%

Section: Tnf-␣ Secretion In Response To Enzymatic Degradation Of Hepamentioning

confidence: 99%

Cutting Edge: An Endogenous Pathway to Systemic Inflammatory Response Syndrome (SIRS)-Like Reactions through Toll-Like Receptor 4

Johnson¹,

Brunn²,

Platt

2004

The Journal of Immunology

Self Cite

222

174

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show abstract

“…Among the few cell types that express heparanase under normal physiological conditions, platelets possess a high heparanase activity and were used as a source for heparanase purification (2,10). In fact, serum heparanase is mainly derived from activated platelets (11). Heparanase was localized to tertiary granules of neutrophils (12,13) and mast cells (7) and was released upon tumor necrosis factor-␣ and calcium ionophore treatments, respectively.…”

mentioning

confidence: 99%

Heparanase Induces Endothelial Cell Migration via Protein Kinase B/Akt Activation

Gingis-Velitski¹,

Zetser²,

Flugelman

et al. 2004

Journal of Biological Chemistry

211

239

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Heparanase is a mammalian endoglycosidase that degrades heparan sulfate (HS) at specific intra-chain sites. Blood-borne neutrophils, macrophages, mast cells, and platelets exhibit heparanase activity that is thought to be stored in specific granules. The degranulated heparanase is implicated in extravasation of metastatic tumor cells and activated cells of the immune system. Degranulation and heparanase release in response to an inflammatory stimulus or platelet activation would facilitate cellular extravasation directly, by altering the composition and structural integrity of the extracellular matrix, or indirectly, by releasing HS-bound proinflammatory cytokines and chemokines. We hypothesized that in addition to such indirect effect, the released heparanase may also locally affect and activate neighboring cells such as endothelial cells. Here, we provide evidence that addition of the 65-kDa latent heparanase to endothelial cells enhances Akt signaling. Heparanase-mediated Akt phosphorylation was independent of its enzymatic activity or the presence of cell membrane HS proteoglycans and was augmented by heparin. Moreover, addition of heparanase stimulated phosphatidylinositol 3-kinasedependent endothelial cell migration and invasion. These results suggest, for the first time, that heparanase activates endothelial cells and elicits angiogenic responses directly. This effect appears to be mediated by as yet unidentified heparanase receptor.Heparanase is an endo-␤-D-glucuronidase capable of cleaving heparan sulfate (HS) 1 side chains at a limited number of sites, yielding HS fragments of still appreciable size (ϳ5-7 kDa) (1-3). Participating in extracellular matrix (ECM) degradation and remodeling, heparanase activity has been traditionally correlated with the metastatic potential of tumor-derived cells (4 -7). Similarly, heparanase has been shown to facilitate cell invasion associated with angiogenesis, autoimmunity, and inflammation (6 -9). Among the few cell types that express heparanase under normal physiological conditions, platelets possess a high heparanase activity and were used as a source for heparanase purification (2, 10). In fact, serum heparanase is mainly derived from activated platelets (11). Heparanase was localized to tertiary granules of neutrophils (12, 13) and mast cells (7) and was released upon tumor necrosis factor-␣ and calcium ionophore treatments, respectively. Heparanase release by degranulation has been implicated in diapedesis and extravasation of a number of immune cells, including neutrophils, macrophages, and lymphocytes (8, 14, 15), while heparanase inhibitors exhibited an anti-inflammatory activity (15). Cleavage of HS side chains by degranulated heparanase during inflammation may facilitate the passage of blood-borne normal and malignant cells into tissues by altering the composition and structural integrity of the subendothelial ECM (1,8,14). In addition, heparanase may facilitate the release of a multitude of HS-bound growth factors, cytokines and chemokines that would, in tu...

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“…Structural modifications of the saccharide residues, especially sulfation, confer manifold biological activities, including regulation of cell adhesion, proliferation, development, anticoagulant, and chemical mediator functions (18 -21). Injury of tissues (22) or exposure of endothelial cells and, perhaps, other cells to activated complement or to neutrophils or platelets causes rapid cleavage and shedding of heparan sulfate proteoglycans and glycosaminoglycan fragments (23)(24)(25)(26). The release of heparan sulfate is postulated to be mediated by proteolytic cleavage of the protein core or by endoglycolytic cleavage of the heparan sulfate chains (25,(27)(28)(29).…”

mentioning

confidence: 99%

Phenotypic and Functional Maturation of Dendritic Cells Mediated by Heparan Sulfate

Kodaira¹,

Nair

Wrenshall

et al. 2000

The Journal of Immunology

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105

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Primary immune responses are thought to be induced by dendritic cells. To promote such responses, dendritic cells must be activated by exogenous agonists, such as LPS, or by products of activated leukocytes, such as TNF-α and IL-1. How dendritic cells might be activated in the absence of exogenous stimuli, or without the immediate presence of activated leukocytes, as might occur in immunity to tumor cells or transplants, is unknown. We postulated that heparan sulfate, an acidic, biologically active polysaccharide associated with cell membranes and extracellular matrices, which is rapidly released under conditions of inflammation and tissue damage, might provide such a stimulus. Incubation of immature murine dendritic cells with heparan sulfate induced phenotypic maturation evidenced by up-regulation of I-A, CD40, CD54 (ICAM-1), CD80 (B7-1), and CD86 (B7-2). Dendritic cells exposed to heparan sulfate exhibited a markedly lowered rate of Ag uptake and increased allostimulatory capacity. Stimulation of dendritic cells with heparan sulfate induced release of TNF-α, IL-1β, and IL-6, although the maturation of dendritic cells was independent of these cytokines. These results suggest that soluble heparan sulfate chains, as products of the degradation of heparan sulfate proteoglycan, might induce maturation of dendritic cells without exogenous stimuli, thus contributing to the generation and maintenance of primary immune responses.

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Regulation of platelet heparanase during inflammation: Role of pH and proteinases

Cited by 75 publications

References 37 publications

Cutting Edge: An Endogenous Pathway to Systemic Inflammatory Response Syndrome (SIRS)-Like Reactions through Toll-Like Receptor 4

Cutting Edge: An Endogenous Pathway to Systemic Inflammatory Response Syndrome (SIRS)-Like Reactions through Toll-Like Receptor 4

Heparanase Induces Endothelial Cell Migration via Protein Kinase B/Akt Activation

Phenotypic and Functional Maturation of Dendritic Cells Mediated by Heparan Sulfate

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