Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.2.2.7 (heparinase)
 1,270 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present report describes a novel function of mast cells that consists of a B cell growth activity. The B cell response occurred without any stimulation or preactivation of mast cells. A small number of mast cells was required, since mast cell/B cell ratios as low as 1/100 to 1/10,000 lead to effective B cell activation. Mast cell-dependent B cell activation resulted, within 48 h of incubation, in blast formation, proliferation, and IgM production. Both low and high density B cells were responsive to mast cells. Supernatants from unstimulated mast cells could also activate B cells, suggesting that a B cell-stimulating activity (MC-BSA) is mediated by a soluble factor(s). The addition of anti-IL-4 or anti-IL-6 mAbs or even proteases to the mast cell-derived supernatants did not alter B cell activation. However, treatment of mast cells with mitomycin C or actinomycin D, or paraformaldehyde fixation totally abrogated MC-BSA. Fractionation of mast cell supernatant by gel filtration chromatography resulted in four peaks, ranging from > 200 to 15 kDa, all of which were biologically active on B cells. Because mast cells are known to continuously release proteoglycans, MC-BSA was subjected to chondroitinase and heparinase treatment, but no significant inhibition of B cell activation was obtained. This direct T cell-independent stimulatory effect of mast cells on B cells could account for a mechanism by which plasma cells are continuously produced in lymphoid organs and particularly in bone marrow.
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PMID:Mouse bone marrow-derived mast cells and mast cell lines constitutively produce B cell growth and differentiation activities. 875 61

Heparan sulfate (HS) proteoglycans play a key role in cell proliferation induced by basic fibroblast growth factor (FGF-2) and other heparin-binding growth factors. To modulate the involvement of HS, we have used a synthetic, nonsulfated polyanionic aromatic compound (RG-13577) that mimics functional features of heparin/HS. FGF-2-stimulated proliferation of vascular endothelial cells was markedly inhibited in the presence of 5-10 microg/ml compound RG-13577 (poly-4-hydroxyphenoxy acetic acid; Mr approximately 5 kD). Direct interaction between RG-13577 and FGF-2 was demonstrated by the ability of the former to compete with heparin on binding to FGF-2. RG-13577 inhibited FGF-2 binding to soluble- and cell surface-FGF receptor 1 (FGFR1). Unlike heparin, RG-13577 alone failed to mediate dimerization of FGF-2. Moreover, it abrogated heparin-mediated dimerization of FGF-2 and FGFR1, as well as FGF-2 mitogenic activity in HS-deficient F32 lymphoid cells. The antiproliferative effect of compound RG-13577 was associated with abrogation of FGF-2-induced tyrosine phosphorylation of FGFR1 and of cytoplasmic proteins involved in FGF-2 signal transduction, such as p90 and mitogen-activated protein kinase. A more effective inhibition of tyrosine phosphorylation was obtained after removal of the cell surface HS by heparinase. In contrast, tyrosine phosphorylation of an approximately 200-kD protein was stimulated by RG-13577, but not by heparin or FGF-2. RG-13577 prevented microvessel outgrowth from rat aortic rings embedded in a collagen gel. Development of nontoxic polyanionic compounds may provide an effective strategy to inhibit FGF-2-induced cell proliferation associated with angiogenesis, arteriosclerosis, and restenosis.
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PMID:Modulation of fibroblast growth factor-2 receptor binding, dimerization, signaling, and angiogenic activity by a synthetic heparin-mimicking polyanionic compound. 912

A microassay was developed to detect human herpesvirus 6 (HHV-6) binding to its cellular receptor using flow cytometry. Comparable results were obtained either by using HHV-6 preparations conjugated with fluorescein isothiocyanate or by indirect immunofluorescent labeling of membrane-bound virus using as primary antibody a monoclonal antibody specific for the HHV-6 gp60/110 envelope glycoprotein. Virus attachment to the plasma membrane was specific and saturable. As expected, among cell lines of various origin, maximum binding was detected on human T-lymphoid cells (HSB-2). Papain digestion of HSB-2 cells prevented HHV-6 attachment and reduced significantly virus infection, indicating the involvement of a protein-based receptor in the attachment step. After removal of the protease, virus receptors were resynthesized and their regeneration was prevented partially by cycloheximide, an inhibitor of protein synthesis. Unexpectedly, only high concentrations (mg/ml) of soluble heparan sulfate and heparin inhibited HHV-6 binding and infection. Under the same conditions, few micrograms (per ml) of heparin suppressed completely herpes simplex type 1 (HSV-1) attachment to the same cell line. Treatment of HSB-2 cells with heparitinase and heparinase, at doses that reduced significantly HSV-1 attachment, had little effect on HHV-6 binding to the cell membrane, indicating a different requirement of heparan sulfate-containing glycosaminoglycans for the two herpesviruses. These data suggest that protein components of the cellular membrane play an essential role in HHV-6 binding and infection while heparan sulfate-glycos-aminoglycans appear to be involved only partially in virus-receptor interaction.
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PMID:Early interactions of human herpesvirus 6 with lymphoid cells: role of membrane protein components and glycosaminoglycans in virus binding. 1107 78

The chemokine CCL21, also known as Exodus-2/6-Ckine/secondary lymphoid-tissue chemokine/T cell activator protein-4, is the most potent stimulator of T cell migration and adhesion yet described. Endothelial heparin-like glycosaminoglycans (GAGs) are thought to present chemokines at sites of inflammation, maintaining a local concentration gradient to which leukocytes can respond. In contrast, this study found that GAGs markedly inhibit the ability of CCL21 to stimulate T cell adhesion and chemotaxis. Enzymes, such as heparinase, that split GAGs into component-sulfated saccharides abrogate this inhibition, suggesting a mechanism for local tissue regulation of CCL21 function. Low-molecular-weight heparins also strongly inhibit CCL21 adhesion and chemotaxis. Therefore, low-molecular-weight heparins may be effective therapeutic agents in decreasing the pathology of T cell-infiltrative autoimmune diseases by targeting the CCL21 regulation of T cell infiltration.
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PMID:Low-molecular-weight heparins inhibit CCL21-induced T cell adhesion and migration. 1206 29

On the surface of smooth muscle cells there are two types of receptors for the mitogenic and angiogenic growth factor fibroblast growth factor-2 (FGF-2); a high affinity tyrosine kinase FGF receptor (FGFR1) and low affinity heparin./heparan-like glycosaminoglycan (HLGAG) component of surface expressed proteoglycans. It is believed that all three components; FGFR1, FGF-2, and the HLGAG chains, must form a ternary complex for maximal cellular stimulation. To carefully examine the role surface HLGAGs play in FGF-2-mediated proliferation of SMCs we have utilized HLGAG degrading enzymes heparinase I, II and III. We report that heparinase treatment of bovine smooth muscle cells inhibits the binding of (125)I-FGF-2 to FGFR1, but does not inhibit FGF-2 induced cellular proliferation. Through the use of both sodium chlorate and FGF-2 mutants with deficient HLGAG-binding capabilities, we show the FGF-2-HLGAG interaction is important for FGF-2's ability to induce SMC proliferation. Finally, we report conditioned media from heparinase treated SMCs is capable of supporting FGF-2 induced proliferation in an HLGAG-free lymphoid F32 cells, suggesting that the heparinase generated fragments are responsible for the proliferative response. The data presented here suggest FGF-2 is capable of stimulating smooth muscle cell proliferation through an FGFR independent, HLGAG dependent mechanism.
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PMID:Heparinase treatment of bovine smooth muscle cells inhibits fibroblast growth factor-2 binding to fibroblast growth factor receptor but not FGF-2 mediated cellular proliferation. 1451 24

The HIV-1 transactivating factor Tat accumulates on the surface of endothelium by interacting with heparan sulfate proteoglycans (HSPGs). Tat also interacts with B-lymphoid Namalwa cells but only when these overexpress HSPGs after syndecan-1 cDNA transfection (SYN-NCs). Accordingly, SYN-NCs, but not mock-transfected cells, adhere to endothelial cells (ECs) when Tat is bound to the surface of either one of the 2 cell types or when SYN-NCs are transfected with a Tat cDNA. Moreover, endogenously produced Tat bound to cell-surface HSPGs mediates cell adhesion of HIV(+) ACH-2 lymphocytes to the endothelium. This heterotypic lymphocyte-EC interaction is prevented by HSPG antagonist or heparinase treatment, but not by integrin antagonists and requires the homodimerization of Tat protein. Tat tethered to the surface of SYN-NCs or of peripheral blood monocytes from healthy donors promotes their transendothelial migration in vitro in response to CXCL12 or CCL5, respectively, and SYN-NC extravasation in vivo in a zebrafish embryo model of inflammation. In conclusion, Tat homodimers bind simultaneously to HSPGs expressed on lymphoid and EC surfaces, leading to HSPG/Tat-Tat/HSPG quaternary complexes that physically link HSPG-bearing lymphoid cells to the endothelium, promoting their extravasation. These data provide new insights about how lymphoid cells extravasate during HIV infection.
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PMID:HIV-1 Tat and heparan sulfate proteoglycan interaction: a novel mechanism of lymphocyte adhesion and migration across the endothelium. 1966 Dec 68

Peyer's patches (PPs) simultaneously initiate active and quiescent immune responses in the gut. The immunological function is achieved by the rigid regulation of cell distribution and trafficking, but how the cell distribution is maintained remains to be elucidated. In this study, we show that binding of stromal cell-derived lymphoid chemokines to conventional dendritic cells (cDCs) is essential for the retention of naive CD4(+) T cells in the interfollicular region (IFR) of PPs. Transitory depletion of CD11c(high) cDCs in mice rapidly impaired the IFR structure in the PPs without affecting B cell follicles or germinal centers, lymphoid chemokine production from stromal cells, or the immigration of naive T cells into the IFRs of PPs. The cDC-orchestrated retention of naive T cells was mediated by heparinase-sensitive molecules that were expressed on cDCs and bound the lymphoid chemokine CCL21 produced from stromal cells. These data collectively reveal that interactions among cDCs, stromal cells, and naive T cells are necessary for the formation of IFRs in the PPs.
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PMID:Critical role of dendritic cells in T cell retention in the interfollicular region of Peyer's patches. 2377 27