Disaccharides derived from heparin or heparan sulfate regulate IL-8 and IL-1β secretion by intestinal epithelial cells

Chowers, Yehuda; Lider, Ofer; Schor, Hagai; Barsnack, Iris; Tal, Ruth; Ariel, Amiram; Bar‐Meir, Simon; Cohen, Irun R.; Cahalon, Liora

doi:10.1053/gast.2001.21202

Cited by 23 publications

(20 citation statements)

References 28 publications

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“…By competing with heparan sulfate on a larger scale, these compounds may interfere with a number of important immunoregulatory mechanisms. Sulfated disaccharides derived from heparin/heparan sulfate have been reported to downregulate the spontaneous and tumor necrosis factor alpha-stimulated secretion of IL-8 and IL-1␤ by intestinal epithelial cells (14). Their mechanism of action, however, has not been established fully (11,32).…”

Section: Discussionmentioning

confidence: 99%

Polyanionic Microbicides Modify Toll-Like Receptor-Mediated Cervicovaginal Immune Responses

Trifonova

Doncel

Fichorova

2009

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 99%

Polyanionic Microbicides Modify Toll-Like Receptor-Mediated Cervicovaginal Immune Responses

Trifonova

Doncel

Fichorova

2009

Antimicrob Agents Chemother

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“…Growing evidence has supported that heparin could modulate immune responses (27)(28)(29), and there are specific binding sites for heparin on monocytes (30). However, there has been no report regarding the effect of heparin on the differentiation of DCs from monocytes.…”

Section: Discussionmentioning

confidence: 99%

Heparin Induces Differentiation of CD1a+ Dendritic Cells from Monocytes: Phenotypic and Functional Characterization

Xia

Kao

2002

The Journal of Immunology

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Dendritic cells (DCs) play important roles in initiation and regulation of immune responses. DCs derived from human monocytes can be classified according to presence of CD1a molecules. Although CD1a+ DCs can be prepared from monocytes in media containing GM-CSF, IL-4, and FCS, it has been reported that CD1a+ DCs could not be easily obtained from monocytes using media containing human serum or plasma. In this study, we demonstrate for the first time that heparin can reliably induce differentiation of CD1a+ DCs from monocytes with or without autologous serum or plasma. The development of CD1a+ DCs is heparin concentration dependent (0–50 U/ml). Comparing with CD1a− DCs developed without heparin, CD1a+ DCs express higher CD40 and CD80 and lower CD86. Both CD1a+ and CD1a− DCs express similar levels of HLA-DR. CD80, CD86, HLA-DR, and CD40 are proportionally up-regulated when both types of DCs are stimulated with LPS or LPS plus IFN-γ. The effect of heparin is neutralized by heparin-binding proteins, such as protamine sulfate, platelet factor-4, and β-thromboglobulin. Functionally, heparin-treated DCs respond to LPS or LPS plus IFN-γ with higher IL-10 and less IL-12 production than heparin-untreated DCs. Heparin-treated DCs are more potent in priming allogeneic and autologous CD4+ T cells to proliferate and to produce both type 1 and type 2 cytokines. The results of our study show that CD1a+ DCs can be prepared from monocytes ex vivo without using xenogeneic serum and may be used for immunotherapy.

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“…The effect of various disaccharides on IL-8 and IL-1␤ secretion by colon cancer cell lines was assessed and again, the most active disaccharide that prevented secretion of these 2 cytokines was 9267. 23 Heparin binds not only to various growth factors, such as FGF, vascular endothelial growth factor, human growth factor, heregulin-␣, amphiregulin and HB-EGF, but also to several receptors, such as the FGF receptor, c-met and the vascular endothelial growth factor receptor. A heparin-binding site has been described for erb-B3 but not for the other receptors of the erb-B family.…”

Section: Discussionmentioning

confidence: 99%

Heparin‐derived disaccharides modulate proliferation and Erb‐B2–mediated signal transduction in colon cancer cell lines

Fishman

Brill

Papa

et al. 2002

Intl Journal of Cancer

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Organ-specific extracellular matrix (ECM) determines metastasis formation by regulating tumor cell proliferation. Hepatocyte-derived ECM enhances proliferation of colon cancer cell lines by increasing expression of tyrosine kinase receptors of the erb-B family. The active components in the ECM are the heparan sulfates, which are highly heterogenous in their chemistry and size. We determined the effect of heparan sulfate disaccharides, of defined chemistry and present in high amounts in the liver heparan sulfate chains, on the proliferation of colon cancer cell lines and investigated the mechanism involved. The low-metastatic cell line KM12 was stimulated to proliferate by a highly sulfated disaccharide, found in the highest amounts in hepatocyte-derived heparan sulfate. Growth of the highly metastatic cell line KM12SM was inhibited by the second most common disaccharide in hepatocyte-derived heparan sulfate. The effect of both disaccharides was not accompanied by changes in the expression of erb-B1, erb-B2, erb-B3 or heregulin-␣. We determined whether the disaccharides modified the signal-transduction pathways mediated by the erb-B receptors. The erb-B2-specific tyrosine kinase inhibitor AG825 abolished the enhancement of KM12 cell proliferation by the stimulatory disaccharide. This disaccharide increased tyrosine phosphorylation of erb-B1 and erb-B2 receptors, effects that were abolished by AG825. Moreover, the disaccharide caused increased expression of cyclin D1 and of activated MAP kinase, again reduced in the presence of the inhibitor AG825. The growth-inhibitory disaccharide reduced phosphorylation of erb-B1, but not of erb-B2, receptors in KM12SM cells. In conclusion, not only hepatocyte-derived heparan sulfate but also disaccharide molecules derived from heparan sulfate can affect colon cancer cell proliferation. Their effect is mediated by modulation of the erb-B signal transduction. © 2002 Wiley-Liss, Inc. Key words: heparin; erb-B2; signal transduction; colon cancer; disaccharide; heparan sulfateSite-specific metastasis, i.e., the propensity of each tumor type to metastasize to certain organs, is strongly dependent on the local environment of various organs colonized by metastatic tumor cells, in particular the extracellular matrix (ECM) of those organs. The organ-specific ECM may have either a stimulatory or an inhibitory effect on tumor cell proliferation. 1,2Previously, we showed that the ability of hepatomas and breast carcinomas to metastasize to a specific organ in vivo depended on in vitro survival of the cells at clonal densities on ECM derived from that organ. 3 The ECM components most active in regulating survival and proliferation were the organ-specific proteoglycans and their effect was due to their glycosaminoglycan chains. 3 Heparin chains affected proliferation by transcriptionally inducing differentiation factors and inhibitory growth factors in the nonmetastatic cells. 4 Previously,we used human colorectal cancer cell lines to assess the role of liver ECM in regulating cell prolifera...

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Disaccharides derived from heparin or heparan sulfate regulate IL-8 and IL-1β secretion by intestinal epithelial cells

Cited by 23 publications

References 28 publications

Polyanionic Microbicides Modify Toll-Like Receptor-Mediated Cervicovaginal Immune Responses

Polyanionic Microbicides Modify Toll-Like Receptor-Mediated Cervicovaginal Immune Responses

Heparin Induces Differentiation of CD1a+ Dendritic Cells from Monocytes: Phenotypic and Functional Characterization

Heparin‐derived disaccharides modulate proliferation and Erb‐B2–mediated signal transduction in colon cancer cell lines

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