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DMBT1 functions as pattern-recognition molecule for poly-sulfated and poly-phosphorylated ligands

End, C. (author), Bikker, F.J. (author), Renner, M. (author), Bergmann, G. (author), Lyer, S. (author), Blaich, S. (author), Hudler, M. (author), Helmke, B. (author), Gassler, N. (author), Autschbach, F. (author), Ligtenberg, A.J.M. (author), Benner, A. (author), Holmskov, U. (author), Schirmacher, P. (author), Nieuw Amerongen, A.V. (author), Rosenstiel, P. (author), Sina, C. (author), Franke, A. (author), Hafner, M. (author), Kioschis, P. (author), Schreiber, S. (author), Poustka, A. (author), Mollenhauer, J. (author)

Deleted in malignant brain tumors 1 (DMBT1) is a secreted glycoprotein displaying a broad bacterial-binding spectrum. Recent functional and genetic studies linked DMBT1 to the suppression of LPS-induced TLR4-mediated NF-kappaB activation and to the pathogenesis of Crohn's disease. Here, we aimed at unraveling the molecular basis of its function...

article 2009

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Proteolytic shedding of the macrophage scavenger receptor CD163 in multiple sclerosis

Fabriek, B.O. (author), Møller, H.J. (author), Vloet, R.P.M. (author), van Winsen, L.M. (author), Hanemaaijer, R. (author), Teunissen, C.E. (author), Uitdehaag, B.M.J. (author), van den Berg, T.K. (author), Dijkstra, C.D. (author), TNO Kwaliteit van Leven (author)

The scavenger receptor CD163 is selectively expressed on tissue macrophages and human monocytes. CD163 has been implicated to play a role in the clearance of hemoglobin and in the regulation of cytokine production by macrophages. Membrane CD163 can be cleaved by matrix metalloproteinases (MMP) resulting in soluble CD163 (sCD163). In the present...

article 2007

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Bioavailability of folic acid from fortified pasteurised and UHT-treated milk in humans

de Jong, R.J. (author), Verwei, M. (author), West, C.E. (author), van Vliet, T. (author), Siebelink, E. (author), van den Berg, H. (author), Castenmiller, J.J.M. (author), TNO Kwaliteit van Leven (author)

Objective: The aim of this study was to investigate whether milk fortified with folic acid enhances the folate status of humans and whether the presence of folate-binding proteins (FBP) in pasteurised milk affects the bioavailability of folic acid from fortified milk. In untreated and pasteurised milk, folate occurs bound to FBP, while FBP is ...

article 2005

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Effect of folate-binding protein on intestinal transport of folic acid and 5-methyltetrahydrofolate across Caco-2 cells

Verwei, M. (author), van den Berg, H. (author), Havenaar, R. (author), Groten, J.P. (author), TNO Defensie en Veiligheid TNO Kwaliteit van Leven (author)

Background: Milk products are a potential matrix for fortification with synthetic folic acid or natural 5-methyltetrahydrofolate (5-CH 3-H4folate) to enhance the daily folate intake. In milk, folate occurs bound to folatebinding proteins (FBP). Our previous studies with an in vitro gastrointestinal model showed that 70% of the initial FBP...

article 2005

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The Binding of Folic Acid and 5-Methyltetrahydrofolate to Folate-Binding Proteins during Gastric Passage Differs in a Dynamic in Vitro Gastrointestinal Model

Verwei, M. (author), Arkbåge, K. (author), Mocking, H. (author), Havenaar, R. (author), Groten, J. (author), TNO Voeding (author)

Despite its low natural folate concentration, milk is responsible for 10-15% of the daily folate intake in countries with a high dairy consumption. Milk products can be considered as a potential matrix for folate fortification, e.g., with synthetic folic acid, to enhance the daily intake of folate. In untreated milk, the natural folate, 5...

article 2004

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Toll-Like Receptor 4 Is Involved in Outward Arterial Remodeling

Hollestelle, S.C.G. (author), de Vries, M.R. (author), van Keulen, J.K. (author), Schoneveld, A.H. (author), Vink, A. (author), Strijder, C.F. (author), van Middelaar, B.J. (author), Pasterkamp, G. (author), Q́uax, P.H.A. (author), de Kleijn, D.P.V. (author), TNO Preventie en Gezondheid (author)

Background-Toll-like receptor 4 (Tlr4) is the receptor for exogenous lipopolysaccharides (LPS). Expression of endogenous Tlr4 ligands, heat shock protein 60 (Hsp60) and extra domain A of fibronectin, has been observed in arthritic and oncological specimens in which matrix turnover is an important feature. In atherosclerosis, outward remodeling...

article 2004

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Aminopeptidase inhibitor bestatin stimulates microvascular endothelial cell invasion in a fibrin matrix

van Hensbergen, Y. (author), Broxterman, H.J. (author), Peters, E. (author), Rana, S. (author), Elderkamp, Y.W. (author), van Hinsbergh, V.W.M. (author), Koolwijk, P. (author), Gaubius Instituut TNO (author)

The aminopeptidase inhibitor bestatin has been shown to have anti-angiogenic effects in a number of model systems. These effects are thought to result from inhibition of CD13 activity. Because tumor angiogenesis can evolve in a fibrin-rich stroma matrix we have studied for the first time the effects of bestatin on microvascular endothelial...

article 2003

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Bioaccessibility of Folic Acid and (6S)-5-Methyltetrahydrofolate Decreases after the Addition of Folate-Binding Protein to Yogurt as Studied in a Dynamic in Vitro Gastrointestinal Model

Arkbåge, K. (author), Verwei, M. (author), Havenaar, R. (author), Witthöft, C. (author), TNO Voeding (author)

Milk products are only moderate sources of folate. Nevertheless, they are of interest due to their content of folate-binding proteins (FBP), which in some studies have been reported to increase folate bioavailability. The effect of FBP on folate bioavailability has been widely discussed. The aim of this study was to investigate the...

article 2003

document

Broad expression of Toll-like receptors in the human central nervous system

Bsibsi, M. (author), Ravid, R. (author), Gveric, D. (author), van Noort, J.M. (author)

The family of Toll-like receptors (TLRs) plays a key role in controlling innate immune responses to a wide variety of pathogen-associated molecules. In this study we investigated expression of TLRs in vitro by purified human microglia, astrocytes, and oligodendrocytes, and in vivo by immunohistochemical examination of brain and spinal cord...

article 2002

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Gene transfer of the urokinase-type plasminogen activator receptor-targeted matrix metalloproteinase inhibitor TIMP-1.ATF suppresses neointima formation more efficiently than tissue inhibitor of metalloproteinase-1

Lamfers, M.L.M. (author), Grimbergen, J.M. (author), Aalders, M.C. (author), Havenga, M.J. (author), de Vries, M.R. (author), Huisman, L.G.M. (author), van Hinsbergh, V.W.M. (author), Quax, P.H.A. (author), Gaubius instituut TNO (author)

Proteases of the plasminogen activator (PA) and matrix metalloproteinase (MMP) system play an important role in smooth muscle cell (SMC) migration and neointima formation after vascular injury. Inhibition of either PAs or MMPs has previously been shown to result in decreased neointima formation in vivo. To inhibit both protease systems...

article 2002

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Proteolysis of the urokinase-type plasminogen activator receptor by metalloproteinase-12: Implication for angiogenesis in fibrin matrices

Koolwijk, P. (author), Sidenius, N. (author), Peters, E. (author), Sier, C.F.M. (author), Hanemaaijer, R. (author), Blasi, F. (author), van Hinsbergh, V.W.M. (author), Gaubius Instituut TNO (author)

Pericellular proteolysis plays an important role in cell migration and the formation of new capillary structures. The plasminogen activator/plasmin and matrix degrading metalloproteinase (MMP) cascades act together in the remodeling of matrix and cell-matrix contacts. Previously we have shown that the formation of capillary structures by human...

article 2001

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Binding and transfer of verocytotoxin by polymorphonuclear leukocytes in hemolytic uremic syndrome

te Loo, D.M.W.M. (author), Monnens, L.A.H. (author), van der Velden, T.J.A.M. (author), Vermeer, M.A. (author), Preyers, F. (author), Demacker, P.N.M. (author), van den Heuvel, L.P.W.J. (author), van Hinsbergh, V.W.M. (author), Gaubius instituut TNO (author)

The hemolytic uremic syndrome (HUS) is the most common cause of acute renal failure in children. The role of a verocytotoxin (VT)-producing Escherichia coli has been strongly implicated in the epidemic form of HUS. Although direct toxicity of VT on glomerular endothelial cells has been demonstrated, it remained still unclear how the VT is...

article 2000

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Urokinase receptor expression on human microvascular endothelial cells is increased by hypoxia: Implications for capillary-like tube formation in a fibrin matrix

Kroon, M.E. (author), Koolwijk, P. (author), van der Vecht, B. (author), van Hinsbergh, V.W.M. (author), Gaubius Instituut TNO (author)

Hypoxia stimulates angiogenesis, the formation of new blood vessels. This study evaluates the direct effect of hypoxia (1% oxygen) on the angiogenic response of human microvascular endothelial cells (hMVECs) seeded on top of a 3-dimensional fibrin matrix, hMVECs stimulated with fibroblast growth factor-2 (FGF-2) or vascular endothelial growth...

article 2000

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Increased clearance explains lower plasma levels of tissue-type plasminogen activator by estradiol: Evidence for potently enhanced mannose receptor expression in mice

Lansink, M. (author), Jong, M. (author), Bijsterbosch, M. (author), Bekkers, M. (author), Toet, K. (author), Havekes, L. (author), Emeis, J. (author), Kooistra, T. (author), Gaubius instituut TNO (author)

Several clinical studies have demonstrated an inverse relationship between circulating levels of estrogen and tissue-type plasminogen activator (t-PA). The present study was designed to test the hypothesis that estrogen lower plasma levels of t-PA by increasing its clearance from the bloodstream. 17α-Ethinyl estradiol (EE) treatment resulted in...

article 1999

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Fibrinolytic activity of human mesothelial cells is counteracted by rapid uptake of tissue-type plasminogen activator

Sitter, T. (author), Toet, K. (author), Quax, P. (author), Kooistra, T. (author), Gaubius instituut TNO (author)

Background. Human mesothelial cells (HMCs) have an important role in maintaining an adequately functioning fibrinolytic system in the peritoneal cavity by secreting the fibrinolytic enzymes tissue-type and urokinase-type plasminogen activator (t-PA and u-PA), as well as a specific PA inhibitor, PA inhibitor type 1 (PAI-1). In this study, we...

article 1999

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Effect of steroid hormones and retinoids on the formation of capillary-like tubular structures of human microvascular endothelial cells in fibrin matrices is related to urokinase expression

Lansink, M. (author), Koolwijk, P. (author), van Hinsbergh, V. (author), Kooistra, T. (author), Gaubius Instituut TNO (author)

Angiogenesis, the formation of new capillary blood vessels, is a feature of a variety of pathological processes. To study the effects of a specific group of hormones (all ligands of the steroid/retinoid/thyroid hormone receptor superfamily) on the angiogenic process in humans, we have used a model system in which human microvascular endothelial...

article 1998

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Binding of human urokinase-type plasminogen activator to its receptor: Residues involved in species specificity and binding

Quax, P.H.A. (author), Grimbergen, J.M. (author), Lansink, M. (author), Bakker, A.H.F. (author), Blatter, M.C. (author), Belin, D. (author), van Hinsbergh, V.W.M. (author), Verheijen, J.H. (author), Gaubius Instituut TNO (author)

Urokinase-type plasminogen activator (UPA), particularly when bound to its receptor (UPAR), is thought to play a major role in local proteolytic processes, thus facilitating cell migration as may occur during angiogenesis, neointima and atherosclerotic plaque formation, and tumor cell invasion. To facilitate understanding of the need and...

article 1998

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Tumor necrosis factor-alpha regulates expression of vascular endothelial growth factor receptor-2 and of its co-receptor neuropilin-1 in human vascular endothelial cells

TNO Preventie en Gezondheid (author), Giraudo, E. (author), Primo, L. (author), Audero, E. (author), Gerber, H.P. (author), Koolwijk, P. (author), Soker, S. (author), Klagsbrun, M. (author), Ferrara, N. (author), Bussolino, F. (author)

Tumor necrosis factor-alpha (TNF-alpha) modulates gene expression in endothelial cells and is angiogenic in vivo. TNF-alpha does not activate in vitro migration and proliferation of endothelium, and its angiogenic activity is elicited by synthesis of direct angiogenic inducers or of proteases. Here, we show that TNF-alpha up-regulates in a dose-...

article 1998

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Mitogenic effects of urokinase on melanoma cells are independent of high affinity binding to the urokinase receptor

Gaubius Instituut TNO (author), Koopman, J.L. (author), Slomp, J. (author), de Bart, A.C.W. (author), Quax, P.H.A. (author), Verheijent, J.H. (author)

The structural and functional properties of the urokinase-type plasminogen activator (u-PA) that are involved in the mitogenic effect of this proteolytic enzyme on human melanoma cells M14 and IF6 and the role of the u-PA receptor (u-PAR) in transducing this signal were analyzed. Native u- PA purified from urine induced a mitogenic response in...

article 1998

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Monoclonal antibodies against the human mannose receptor as a specific marker in flow cytometry and immunohistochemistry for macrophages

Noorman, F. (author), Braat, E.A.M. (author), Barrett-Bergshoeff, M.M. (author), Barbé, E. (author), van Leeuwen, A. (author), Lindeman, J. (author), Rijken, D.C. (author), TNO Preventie en Gezondheid (author)

Recently we developed mouse monocloual antibodies (mAb) against the isolated human 175-kDa mannose receptor. In the present study we tested whether these mAb are suitable for the detection of the mannose receptor on cultured macrophages using flow cytometry and on cells in human tissues using immunohistochemistry. Human monocytes did not react...

article 1997