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Linda G Baum - One of the best experts on this subject based on the ideXlab platform.
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timing of Galectin 1 exposure differentially modulates nipah virus entry and syncytium formation in endothelial cells
Journal of Virology, 2015Co-Authors: Omai B Garner, Arnold Park, Olivier Pernet, Hector C Aguilar, Thomas A Bowden, Alexander N Freiberg, Linda G BaumAbstract:Nipah virus (NiV) is a deadly emerging enveloped paramyxovirus that primarily targets human endothelial cells. Endothelial cells express the innate immune effector Galectin-1 that we have previously shown can bind to specific N-glycans on the NiV envelope fusion glycoprotein (F). NiV-F mediates fusion of infected endothelial cells into syncytia, resulting in endothelial disruption and hemorrhage. Galectin-1 is an endogenous carbohydrate-binding protein that binds to specific glycans on NiV-F to reduce endothelial cell fusion, an effect that may reduce pathophysiologic sequelae of NiV infection. However, Galectins play multiple roles in regulating host-pathogen interactions; for example, Galectins can promote attachment of HIV to T cells and macrophages and attachment of HSV-1 to keratinocytes but can also inhibit influenza entry into airway epithelial cells. Using live Nipah virus, in the present study, we demonstrate that Galectin-1 can enhance NiV attachment to and infection of primary human endothelial cells by bridging glycans on the viral envelope to host cell glycoproteins. In order to exhibit an enhancing effect, Galectin-1 must be present during the initial phase of virus attachment; in contrast, addition of Galectin-1 postinfection results in reduced production of progeny virus and syncytium formation. Thus, Galectin-1 can have dual and opposing effects on NiV infection of human endothelial cells. While various roles for Galectin family members in microbial-host interactions have been described, we report opposing effects of the same Galectin family member on a specific virus, with the timing of exposure during the viral life cycle determining the outcome.Nipah virus is an emerging pathogen that targets endothelial cells lining blood vessels; the high mortality rate (up to 70%) in Nipah virus infections results from destruction of these cells and resulting catastrophic hemorrhage. Host factors that promote or prevent Nipah virus infection are not well understood. Endogenous human lectins, such as Galectin-1, can function as pattern recognition receptors to reduce infection and initiate immune responses; however, lectins can also be exploited by microbes to enhance infection of host cells. We found that Galectin-1, which is made by inflamed endothelial cells, can both promote Nipah virus infection of endothelial cells by "bridging" the virus to the cell, as well as reduce production of progeny virus and reduce endothelial cell fusion and damage, depending on timing of Galectin-1 exposure. This is the first report of spatiotemporal opposing effects of a host lectin for a virus in one type of host cell.
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vegfr1 and vegfr2 involvement in extracellular Galectin 1 and Galectin 3 induced angiogenesis
PLOS ONE, 2013Co-Authors: Nicky Dhaene, Linda G Baum, Christine Decaestecker, S Sauvage, Calliope Maris, Ivan Adanja, Marie Le Mercier, Isabelle SalmonAbstract:Aim:Accumulating evidence suggests that extracellular Galectin-1 and Galectin-3 promote angiogenesis. Increased expression of Galectin-1 and/or Galectin-3 has been reported to be associated with tumour progression. Thus, it is critical to identify their influence on angiogenesis.Methods:We examined the individual and combined effects of Galectin-1 and Galectin-3 on endothelial cell (EC) growth and tube formation using two EC lines, EA.hy926 and HUVEC. The activation of vascular endothelial growth factor receptors (VEGFR1 and VEGFR2) was determined by ELISA and Western blots. We evaluated the VEGFR1 and VEGFR2 levels in endosomes by proximity ligation assay.Results:We observed different responses to exogenous Galectins depending on the EC line. An enhanced effect on EA.hy926 cell growth and tube formation was observed when both Galectins were added together. Focusing on this enhanced effect, we observed that together Galectins induced the phosphorylation of both VEGFR1 and VEGFR2, whereas Galectin-1 and -3 alone induced VEGFR2 phosphorylation only. In the same way, the addition of a blocking VEGFR1 antibody completely abolished the increase in tube formation induced by the combined addition of both Galectins. In contrast, the addition of a blocking VEGFR2 antibody only partially inhibited this effect. Finally, the addition of both Galectins induced a decrease in the VEGFR1 and VEGFR2 endocytic pools, with a significantly enhanced effect on the VEGFR1 endocytic pool. These results suggest that the combined action of Galectin-1 and Galectin-3 has an enhanced effect on angiogenesis via VEGFR1 activation, which could be related to a decrease in receptor endocytosis. © 2013 D'Haene et al.
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n and o glycans modulate Galectin 1 binding cd45 signaling and t cell death
Journal of Biological Chemistry, 2010Co-Authors: Lesley A Earl, Linda G BaumAbstract:Galectin-1, a β-galactoside-binding protein highly expressed in the thymus, induces apoptosis of specific thymocyte subsets and activated T cells. Galectin-1 binds to N- and O-glycans on several glycoprotein receptors, including CD7, CD43, and CD45. Here we show that Galectin-1 signaling through CD45, which carries both N- and O-glycans, is regulated by CD45 isoform expression, core 2 O-glycan formation and the balance of N-glycan sialylation. Regulation of Galectin-1 T cell death by O-glycans is mediated through CD45 phosphatase activity. While Galectin-1 signaling in cells expressing low molecular weight isoforms of CD45 requires expression of core 2 O-glycans (high affinity ligands for Galectin-1), Galectin-1 signaling in cells expressing a high molecular weight isoform of CD45 does not require core 2 O-glycans, suggesting that a larger amount of core 1 O-glycans (low affinity ligands for Galectin-1) is sufficient to overcome lack of core 2 O-glycans. Furthermore, regulation of Galectin-1 signaling by α2,6-sialylation of N-glycans is not solely dependent on CD45 phosphatase activity and can be modulated by the relative expression of enzymes that attach sialic acid in an α2,6- or α2,3-linkage. Thus, N- and O-glycans modulate Galectin-1 T cell death by distinct mechanisms, and different glycosylation events can render thymocytes susceptible or resistant to Galectin-1.
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Galectin 1 co clusters cd43 cd45 on dendritic cells and induces cell activation and migration through syk and protein kinase c signaling
Journal of Biological Chemistry, 2009Co-Authors: J Fulcher, Linda G Baum, Mabel Pang, Margaret H Chang, Shuo Wang, Tim Almazan, Sara T Hashimi, Anna U Eriksson, Xiangshu Wen, Ram Raj SinghAbstract:Galectin-1 is a galactoside-binding lectin expressed in multiple tissues that has pleiotropic immunomodulatory functions. We previously showed that Galectin-1 activates human monocyte-derived dendritic cells (MDDCs) and triggers a specific genetic program that up-regulates DC migration through the extracellular matrix, an integral property of mucosal DCs. Here, we identify the Galectin-1 receptors on MDDCs and immediate downstream effectors of Galectin-1-induced MDDC activation and migration. Galectin-1 binding to surface CD43 and CD45 on MDDCs induced an unusual unipolar co-clustering of these receptors and activates a dose-dependent calcium flux that is abrogated by lactose. Using a kinome screen and a systems biology approach, we identified Syk and protein kinase C tyrosine kinases as mediators of the DC activation effects of Galectin-1. Galectin-1, but not lipopolysaccharide, stimulated Syk phosphorylation and recruitment of phosphorylated Syk to the CD43 and CD45 co-cluster on MDDCs. Inhibitors of Syk and protein kinase C signaling abrogated Galectin-1-induced DC activation as monitored by interleukin-6 production; and MMP-1, -10, and -12 gene up-regulation; and enhanced migration through the extracellular matrix. The latter two are specific features of Galectin-1-activated DCs. Interestingly, we also found that Galectin-1 can prime DCs to respond more quickly to low dose lipopolysaccharide stimulation. Finally, we underscore the biological relevance of Galectin-1-enhanced DC migration by showing that intradermal injection of Galectin-1 in MRL-fas mice, which have a defect in skin DC emigration, increased the in vivo migration of dermal DCs to draining lymph nodes.
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endogenous Galectin 1 enforces class i restricted tcr functional fate decisions in thymocytes
Blood, 2008Co-Authors: Scot D Liu, Linda G Baum, Françoise Poirier, Mabel Pang, Chan C Whiting, Tamar Tomassian, Stephanie J Bissel, Valeri V Mossine, Margaret E Huflejt, Carrie M MiceliAbstract:During thymocyte development, the T-cell receptor (TCR) can discriminate major histocompatibility complex (MHC)/peptide ligands over a narrow range of affinities and translate subtle differences into functional fate decisions. How small differences in TCR input are translated into absolute differences in functional output is unclear. We examined the effects of Galectin-1 ablation in the context of class-I–restricted thymocyte development. Galectin-1 expression opposed TCR partial agonist-driven positive selection, but promoted TCR agonist-driven negative selection of conventional CD8+ T cells. Galectin-1 expression also promoted TCR agonist-driven CD8αα intestinal intraepithelial lymphocytes (IEL) development. Recombinant Galectin-1 enhanced TCR binding to agonist/MHC complexes and promoted a negative-selection-signaling signature, reflected in intensified rapid and transient extracellular signal-regulated kinase (ERK) activation. In contrast, Galectin-1 expression antagonized ERK activity in thymocytes undergoing positive selection. We propose that Galectin-1 aids in discriminating TCR-directed fate decisions by promoting TCR binding to agonist/MHC complexes and enforcing agonist-driven signals, while opposing partial-agonist signals. In this way, Galectin-1 widens the distinction between TCR-directed functional fate cues.
Hans-joachim Gabius - One of the best experts on this subject based on the ideXlab platform.
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tumor suppressor p16ink4a downregulation of Galectin 3 an endogenous competitor of the pro anoikis effector Galectin 1 in a pancreatic carcinoma model
FEBS Journal, 2010Co-Authors: Hugo Sanchezruderisch, Sabine André, Christian Fischer, Katharina Detjen, M Welzel, Anja Wimmel, Joachim C Manning, Hans-joachim GabiusAbstract:The tumor suppressor p16INK4a has functions beyond cell-cycle control via cyclin-dependent kinases. A coordinated remodeling of N- and O-glycosylation, and an increase in the presentation of the endogenous lectin Galectin-1 sensing these changes on the surface of p16INK4a-expressing pancreatic carcinoma cells (Capan-1), lead to potent pro-anoikis signals. We show that the p16INK4a-dependent impact on growth-regulatory lectins is not limited to Galectin-1, but also concerns Galectin-3. By monitoring its expression in relation to p16INK4a status, as well as running anoikis assays with Galectin-3 and cell transfectants with up- or downregulated lectin expression, a negative correlation between anoikis and the presence of this lectin was established. Nuclear run-off and northern blotting experiments revealed an effect of the presence of p16INK4a on steady-state levels of Galectin-3-specific mRNA that differed from decreasing the transcriptional rate. On the cell surface, Galectin-3 interferes with Galectin-1, which initiates signaling toward its pro-anoikis activity via caspase-8 activation. The detected opposite effects of p16INK4a at the levels of growth-regulatory Galectins-1 and -3 shift the status markedly towards the Galectin-1-dependent pro-anoikis activity. A previously undescribed orchestrated fine-tuning of this effector system by a tumor suppressor is discovered.
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inhibition of human retinal pigment epithelial cell attachment spreading and migration by the human lectin Galectin 1
Molecular Vision, 2009Co-Authors: Claudia S Algepriglinger, Sabine André, Thomas C Kreutzer, Cornelia A Deeg, Anselm Kampik, Marcus Kernt, Harald Schoffl, Siegfried G Priglinger, Hans-joachim GabiusAbstract:Purpose: Adhesion and migration of dislocated retinal pigment epithelial (RPE) cells are initial steps in the pathogenesis of proliferative vitreoretinopathy (PVR). The role of the endogenous lectin, Galectin-1, in attachment, spreading, and migration of human RPE cells was investigated from a therapeutic perspective. Methods: Human RPE cells were treated with Galectin-1 concentrations that ranged 0–250 µg/ml. Cell viability was tested by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide (MTT) assay. Galectin-1 binding to the RPE cells was investigated by immunocytochemistry. Attachment of RPE cells was assessed on 96-well plates coated with laminin, or fibronectin, or Galectin-1, or the glycoprotein-lectin combinations and subsequent MTT-testing. RPE migration in the absence or presence of Galectin-1 on the respective substrates was tested using a modified Boyden chamber assay with platelet derived growth factor (PDGF)-BB as the chemoattractant. Cellular spreading was characterized by cytoplasmic halo formation of RPE cells after three hours in contact with the surface coating. Results: Galectin-1 bound to the cell surface. Binding could be inhibited by a β-galactoside. MTT assays revealed no toxicity within control limits for the concentration range tested. When added to the medium, Galectin-1 dose-dependently inhibited RPE cell attachment, spreading, and migration by more than 70%, irrespective of the substratum tested. When coated onto the plastic surface, Galectin-1 alone impaired spreading and migration of RPE cells, and reduced attachment to and migration on fibronectin by up to 80%. Conclusions: Galectin-1 inhibits RPE cell attachment, migration, and spreading in vitro with no apparent cytotoxicity. This activity of the endogenous effector deserves consideration as a potential therapeutic agent for the prevention of PVR.
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Galectin 1 knocking down in human u87 glioblastoma cells alters their gene expression pattern
Biochemical and Biophysical Research Communications, 2005Co-Authors: Isabelle Camby, Christine Decaestecker, Herbert Kaltner, Hans-joachim Gabius, Florence Lefranc, Robert KissAbstract:We have previously reported that (i) progression of malignancy in patients bearing astrocytic tumors correlates with increased tumor levels of Galectin-1; (ii) in vitro addition of purified Galectin-1 to U87 human glioblastoma cells enhances tumor cell motility; and (iii) conversely, knocking down Galectin-1 expression in this cell line by stable transfection with antisense Galectin-1 mRNA impairs motility and delays mortality after their intracranial grafting to nude mice. We here used cDNA microarray analysis to compare the effect on gene expression of stable transfection with antisense Galectin-1 vector to mock-transfected and wild-type cells. Among the 631 spots probing genes potentially involved in cancer that were valid for analysis on all the arrays the expression of 86 genes was increased at least 2-fold. Confirmation of increased protein levels was provided by immunocytochemistry for p21waf/cip1, cullin-2, p53, ADAM-15, and MAP-2. Major differences in the expression patterns of ADAM-15 and the actin stress fiber organization were also observed. U87 cells stably deficient for Galectin-1 expression were significantly less motile than control. We conclude that the stable inhibition of Galectin-1 expression alters the expression of a number of genes that either directly or indirectly influence adhesion, motility and invasion of human glioblastoma cells.
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Galectin-1(L11A) Predicted from a Computed Galectin-1 Farnesyl-Binding Pocket Selectively Inhibits Ras-GTP
Cancer research, 2004Co-Authors: Barak Rotblat, Hagit Niv, Sabine André, Herbert Kaltner, Hans-joachim Gabius, Yoel KloogAbstract:Ras biological activity necessitates membrane anchorage that depends on the Ras farnesyl moiety and is strengthened by Ras/Galectin-1 interactions. We identified a hydrophobic pocket in Galectin-1, analogous to the Cdc42 geranylgeranyl-binding cavity in RhoGDI, possessing homologous isoprenoid-binding residues, including the critical L11, whose RhoGDI L77 homologue changes dramatically on Cdc42 binding. By substituting L11A, we obtained a dominant interfering Galectin-1 that possessed normal carbohydrate-binding capacity but inhibited H-Ras GTP-loading and extracellular signal-regulated kinase activation, dislodged H-Ras(G12V) from the cell membrane, and attenuated H-Ras(G12V) fibroblast transformation and PC12-cell neurite outgrowth. Thus, independently of carbohydrate binding, Galectin-1 cooperates with Ras, whereas Galectin-1(L11A) inhibits it.
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Galectin 1 augments ras activation and diverts ras signals to raf 1 at the expense of phosphoinositide 3 kinase
Journal of Biological Chemistry, 2002Co-Authors: Galit Eladsfadia, Hans-joachim Gabius, Eyal Ballan, Ronit Haklai, Yoel KloogAbstract:Ras proteins activate diverse effector molecules. Depending on the cellular context, Ras activation may have different biological consequences: induction of cell proliferation, senescence, survival, or death. Augmentation and selective activation of particular effector molecules may underlie various Ras actions. In fact, Ras effector-loop mutants interacting with distinctive effectors provide evidence for such selectivity. Interactions of active Ras with escort proteins, such as Galectin-1, could also direct Ras selectivity. Here we show that in comparison with Ras transfectants, H-Ras/Galectin-1 or K-Ras4B/Galectin-1 co-transfectants exhibit enhanced and prolonged epidermal growth factor (EGF)-stimulated increases in Ras-GTP, Raf-1 activity, and active extracellular signal-regulated kinase. Galectin-1 antisense RNA inhibited these EGF responses. Conversely, Ras and Galectin-1 co-transfection inhibited the EGF-stimulated increase in phosphoinositide 3-kinase (PI3K) activity. Galectin-1 transfection also inhibited Ras(G12V)-induced PI3K but not Raf-1 activity. Galectin-1 co-immunoprecipitated with Ras(G12V) or with Ras(G12V/T35S) that activate Raf-1 but not with Ras(G12V/Y40C) that activates PI3K. Thus, Galectin-1 binds active Ras and diverts its signal to Raf-1 at the expense of PI3K. This demonstrates a novel mechanism controlling the duration and selectivity of the Ras signal. Ras gains selectivity when it is associated with Galectin-1, mimicking the selectivity of Ras(T35S), which activates Raf-1 but not PI3K.
Dong Tang - One of the best experts on this subject based on the ideXlab platform.
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apoptosis and anergy of t cell induced by pancreatic stellate cells derived Galectin 1 in pancreatic cancer
Tumor Biology, 2015Co-Authors: Dong Tang, Jun Gao, Sen Wang, Zhongxu Yuan, Yang Chong, Xuetong Jiang, Wei Yin, Yi Miao, Daorong Wang, Kuirong JiangAbstract:Galectin-1, a β-galactoside-binding protein implicated in cancer cell immune privilege, was highly expressed in activated pancreatic stellate cells (PSCs). This study was designed to investigate the relationship between PSC-derived Galectin-1 and tumor immunity in pancreatic cancer. Isolated PSCs were identified as normal pancreas cells (hNPSCs) or pancreatic cancer cells (hCaPSCs) by immunohistochemical staining for α-SMA and vimentin, and Galectin-1 expression was evaluated by Western blotting and quantitative RT-PCR. Apoptosis, caspase activity, and cytokine production (IL-6, IL-10, TNF-β, and IFN-γ) of T cells co-cultured with PSCs were evaluated, and immunohistochemical staining of Galectin-1 was correlated with CD3 and clinicopathological variables in 66 pancreatic cancer and 10 normal pancreatic tissue samples. hCaPSCs exhibited higher Galectin-1 expression than did hNPSCs, and hCaPSCs induced higher levels of apoptosis in T cells following co-culture. hCaPSCs activated caspase-9 and caspase-3 in the mitochondrial apoptotic pathway and stimulated secretion of Th2 cytokines (IL-6 and IL-10) but decreased secretion of Th1 cytokines (TNF-β and IFN-γ), compared with hNPSCs. Immunohistochemical staining indicated that Galectin-1 and CD3 were more highly expressed in pancreatic cancer tissue. Galectin-1 expression was highest in poorly differentiated pancreatic cancer cells and lowest in well-differentiated pancreatic cancer cells and was associated with tumor size, lymph node metastasis, differentiation, and UICC stage. However, CD3 expression showed the opposite trend and was highest in well-differentiated pancreatic cancer cells and was associated with tumor differentiation and UICC stage. High expression of Galectin-1 was associated with short survival, as was low expression of CD3. hCaPSC-derived Galectin-1 enhanced apoptosis and anergy of T cells in pancreatic cancer, which contributes to the immune escape of pancreatic cancer cells.
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Pancreatic satellite cells derived Galectin-1 increase the progression and less survival of pancreatic ductal adenocarcinoma. PLoS One
2014Co-Authors: Dong Tang, Jun Gao, Sen Wang, Zhongxu Yuan, Yi Miao, Jingqiu Zhang, Sujun Gao, Daorong WangAbstract:Background: Galectin-1, a member of carbohydrate-binding proteins with a polyvalent function on tumor progression, was found strongly expressed in pancreatic satellite cells (PSCs), which partner in crime with cancer cells and promote the development of pancreatic ductal adenocarcinoma (PDAC). We evaluated the effects of PSCs derived Galectin-1 on the progression of PDAC, as well as the tumor establishment and development in mouse xenografts. Methods: The relationship between immunohistochemistry staining intensity of Galectin-1 and clinicopathologic variables were assessed in 66 PDAC tissues, 18 chronic pancreatitis tissues and 10 normal controls. The roles of PSCs isolated from PDAC and normal pancreas on the proliferative activity, MMP2 and MMP9 expression, and the invasion of CFPAC-1 in the co-cultured system, as well as on the tumor establishment and development in mouse xenografts by mixed implanting with CFPAC-1 subcutaneously were evaluated. Results: Galectin-1 expression was gradually increased from normal pancreas (negative), chronic pancreatitis (weak) to PDAC (strong), in which Galectin-1 expression was also increased from well, moderately to poorly differentiated PDAC. Galectin-1 staining intensity of pancreatic cancer tissue was associated with increase in tumor size, lymph node metastasis, perineural invasion and differentiation and UICC stage, and served as the independent prognostic indicator of poor surviva
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high expression of Galectin 1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer
International Journal of Cancer, 2012Co-Authors: Dong Tang, Zhongxu Yuan, Yi Miao, Xiaofeng Xue, Ye Zhang, Hui Wang, Minyong Chen, Jishu Wei, Yi Zhu, Kuirong JiangAbstract:Galectin-1 is implicated in making tumor cells immune privileged, in part by regulating the survival of infiltrating T cells. Galectin-1 is strongly expressed in activated pancreatic stellate cells (PSCs); however, whether this is linked to tumor cell immune escape in pancreatic cancer is unknown. Galectin-1 was knocked down in PSCs isolated from pancreatic tissues using small interfering RNA (siRNA), or overexpressed using recombinant lentiviruses, and the PSCs were cocultured with T cells. CD3+, CD4+ and CD8+ T cell apoptosis was detected by flow cytometry; T cell IL-2, IL-4, IL-5 and INF-γ production levels were quantified using ELISA. Immunohistochemical analysis showed increased numbers of PSCs expressed Galectin-1 (p < 0.01) and pancreatic cancers had increased CD3+ T cell densities (p < 0.01) compared to normal pancreas or chronic pancreatitis samples. In coculture experiments, PSCs that overexpressed Galectin-1 induced apoptosis of CD4+ T cells (p < 0.01) and CD8+ T cells (p < 0.05) significantly, compared to normal PSCs. Knockdown of Galectin-1 in PSCs increased CD4+ T cell (p < 0.01) and CD8+ T cell viability (p < 0.05). Supernatants from T cells cocultured with PSCs that overexpressed Galectin-1 contained significantly increased levels of Th2 cytokines (IL-4 and IL-5, p < 0.01) and decreased Th1 cytokines (IL-2 and INF-γ, p < 0.01). However, the knockdown of PSC Galectin-1 had the opposite effect on Th1 and Th2 cytokine secretion. Our study suggests that the overexpression of Galectin-1 in PSCs induced T cell apoptosis and Th2 cytokine secretion, which may regulate PSC-dependent immunoprivilege in the pancreatic cancer microenvironment. Galectin-1 may provide a novel candidate target for pancreatic cancer immunotherapy.
Kuirong Jiang - One of the best experts on this subject based on the ideXlab platform.
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apoptosis and anergy of t cell induced by pancreatic stellate cells derived Galectin 1 in pancreatic cancer
Tumor Biology, 2015Co-Authors: Dong Tang, Jun Gao, Sen Wang, Zhongxu Yuan, Yang Chong, Xuetong Jiang, Wei Yin, Yi Miao, Daorong Wang, Kuirong JiangAbstract:Galectin-1, a β-galactoside-binding protein implicated in cancer cell immune privilege, was highly expressed in activated pancreatic stellate cells (PSCs). This study was designed to investigate the relationship between PSC-derived Galectin-1 and tumor immunity in pancreatic cancer. Isolated PSCs were identified as normal pancreas cells (hNPSCs) or pancreatic cancer cells (hCaPSCs) by immunohistochemical staining for α-SMA and vimentin, and Galectin-1 expression was evaluated by Western blotting and quantitative RT-PCR. Apoptosis, caspase activity, and cytokine production (IL-6, IL-10, TNF-β, and IFN-γ) of T cells co-cultured with PSCs were evaluated, and immunohistochemical staining of Galectin-1 was correlated with CD3 and clinicopathological variables in 66 pancreatic cancer and 10 normal pancreatic tissue samples. hCaPSCs exhibited higher Galectin-1 expression than did hNPSCs, and hCaPSCs induced higher levels of apoptosis in T cells following co-culture. hCaPSCs activated caspase-9 and caspase-3 in the mitochondrial apoptotic pathway and stimulated secretion of Th2 cytokines (IL-6 and IL-10) but decreased secretion of Th1 cytokines (TNF-β and IFN-γ), compared with hNPSCs. Immunohistochemical staining indicated that Galectin-1 and CD3 were more highly expressed in pancreatic cancer tissue. Galectin-1 expression was highest in poorly differentiated pancreatic cancer cells and lowest in well-differentiated pancreatic cancer cells and was associated with tumor size, lymph node metastasis, differentiation, and UICC stage. However, CD3 expression showed the opposite trend and was highest in well-differentiated pancreatic cancer cells and was associated with tumor differentiation and UICC stage. High expression of Galectin-1 was associated with short survival, as was low expression of CD3. hCaPSC-derived Galectin-1 enhanced apoptosis and anergy of T cells in pancreatic cancer, which contributes to the immune escape of pancreatic cancer cells.
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high expression of Galectin 1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer
International Journal of Cancer, 2012Co-Authors: Dong Tang, Zhongxu Yuan, Yi Miao, Xiaofeng Xue, Ye Zhang, Hui Wang, Minyong Chen, Jishu Wei, Yi Zhu, Kuirong JiangAbstract:Galectin-1 is implicated in making tumor cells immune privileged, in part by regulating the survival of infiltrating T cells. Galectin-1 is strongly expressed in activated pancreatic stellate cells (PSCs); however, whether this is linked to tumor cell immune escape in pancreatic cancer is unknown. Galectin-1 was knocked down in PSCs isolated from pancreatic tissues using small interfering RNA (siRNA), or overexpressed using recombinant lentiviruses, and the PSCs were cocultured with T cells. CD3+, CD4+ and CD8+ T cell apoptosis was detected by flow cytometry; T cell IL-2, IL-4, IL-5 and INF-γ production levels were quantified using ELISA. Immunohistochemical analysis showed increased numbers of PSCs expressed Galectin-1 (p < 0.01) and pancreatic cancers had increased CD3+ T cell densities (p < 0.01) compared to normal pancreas or chronic pancreatitis samples. In coculture experiments, PSCs that overexpressed Galectin-1 induced apoptosis of CD4+ T cells (p < 0.01) and CD8+ T cells (p < 0.05) significantly, compared to normal PSCs. Knockdown of Galectin-1 in PSCs increased CD4+ T cell (p < 0.01) and CD8+ T cell viability (p < 0.05). Supernatants from T cells cocultured with PSCs that overexpressed Galectin-1 contained significantly increased levels of Th2 cytokines (IL-4 and IL-5, p < 0.01) and decreased Th1 cytokines (IL-2 and INF-γ, p < 0.01). However, the knockdown of PSC Galectin-1 had the opposite effect on Th1 and Th2 cytokine secretion. Our study suggests that the overexpression of Galectin-1 in PSCs induced T cell apoptosis and Th2 cytokine secretion, which may regulate PSC-dependent immunoprivilege in the pancreatic cancer microenvironment. Galectin-1 may provide a novel candidate target for pancreatic cancer immunotherapy.
Richard D Cummings - One of the best experts on this subject based on the ideXlab platform.
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Galectin 1 exerts inhibitory effects during denv 1 infection
PLOS ONE, 2014Co-Authors: Karina Alves Toledo, Richard D Cummings, Marise Lopes Fermino, Camillo Del Cistia Andrade, Thalita B Riul, Renata Tome Alves, Vanessa Danielle Menjon Muller, Raquel Rinaldi Russo, Sean R Stowell, Victor Hugo AquinoAbstract:Dengue virus (DENV) is an enveloped RNA virus that is mosquito-transmitted and can infect a variety of immune and non-immune cells. Response to infection ranges from asymptomatic disease to a severe disorder known as dengue hemorrhagic fever. Despite efforts to control the disease, there are no effective treatments or vaccines. In our search for new antiviral compounds to combat infection by dengue virus type 1 (DENV-1), we investigated the role of Galectin-1, a widely-expressed mammalian lectin with functions in cell-pathogen interactions and immunoregulatory properties. We found that DENV-1 infection of cells in vitro exhibited caused decreased expression of Gal-1 in several different human cell lines, suggesting that loss of Gal-1 is associated with virus production. In test of this hypothesis we found that exogenous addition of human recombinant Gal-1 (hrGal-1) inhibits the virus production in the three different cell types. This inhibitory effect was dependent on hrGal-1 dimerization and required its carbohydrate recognition domain. Importantly, the inhibition was specific for hrGal-1, since no effect was observed using recombinant human Galectin-3. Interestingly, we found that hrGal-1 directly binds to dengue virus and acts, at least in part, during the early stages of DENV-1 infection, by inhibiting viral adsorption and its internalization to target cells. To test the in vivo role of Gal-1 in DENV infection, Gal-1-deficient-mice were used to demonstrate that the expression of endogenous Galectin-1 contributes to resistance of macrophages to in vitro-infection with DENV-1 and it is also important to physiological susceptibility of mice to in vivo infection with DENV-1. These results provide novel insights into the functions of Gal-1 in resistance to DENV infection and suggest that Gal-1 should be explored as a potential antiviral compound.
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Galectin 1 a beta galactoside binding lectin in chinese hamster ovary cells ii localization and biosynthesis
Journal of Biological Chemistry, 1995Co-Authors: Moonjae Cho, Richard D CummingsAbstract:In the accompanying study (Cho, M., and Cummings, R. D. (1995) J. Biol. Chem. 270, 5198-5206), we reported that Chinese hamster ovary (CHO) cells synthesize Galectin-1. We have now used several approaches to define the subcellular location and biosynthesis of Galectin-1 in these cells. Galectin-1 was present on the cell surface, as assessed by immunofluorescent staining with monospecific antibody to the protein. Quantitation of the surface-localized Galectin-1 was achieved by metabolically radiolabeling cells with [35S]Met/Cys and measuring the amount of lectin (i) sensitive to trypsin, (ii) accessible to biotinylating reagents, and (iii) accessible to the haptenic disaccharide lactose. By all three procedures, approximately 1/2 of the radiolabeled Galectin-1 associated with cells was shown to be on the cell surface with the remainder intracellular. The kinetics of externalization of Galectin-1 was monitored by pulse-chase radiolabeling, and it was shown that cells secrete the protein with a t1/2 approximately 20 h. The cell surface form of Galectin-1 in CHO cells was active and bound to surface glycoconjugates, but lectin accumulating in the culture media was inactive. Lectin synthesized by mutant Lec8 CHO cells, which are unable to galactosylate glycoproteins was not found on the surface and quantitatively accumulated in the media in an inactive form. Taken together, our results demonstrate that Galectin-1 is quantitatively externalized by CHO cells and can associate with surface glycoconjugates where the lectin activity is stabilized.
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Galectin 1 a beta galactoside binding lectin in chinese hamster ovary cells i physical and chemical characterization
Journal of Biological Chemistry, 1995Co-Authors: Moonjae Cho, Richard D CummingsAbstract:We report our studies on the characterization of an approximately 14-kDa lectin, termed Galectin-1 that we have found to be expressed by Chinese hamster ovary (CHO) cells. cDNA for Galectin-1 from CHO cells was prepared and sequenced, and a recombinant form (rGal-1) was expressed in Escherichia coli. A mutated form of the protein that fully retained activity was also constructed (termed C2SrGal-1) in which Cys-2 was changed to Ser-2. rGal-1 was stable in the presence of reducing agent, but it quickly lost all activity in the absence of reducing agent. In contrast, glycoprotein ligands, such as basement membrane laminin, stabilized the activity of rGal-1 in the absence of reducing agent (t1/2 = 2 weeks). C2SrGal-1 was stable in the presence or absence of either ligand or reducing agent. Unexpectedly, Galectin-1 was found to exist in a reversible and active monomer-dimer equilibrium with a Kd approximately 7 microM and an equilibration time of t1/2 approximately 10 h. Addition of haptenic sugars did not affect this equilibrium. Galectin-1 isolated from the cytosol of CHO cells was found to exist as monomers and dimers. These studies demonstrate that Galectin-1 binding to a biological ligand stabilizes its activity and that the monomer/dimer state of the protein is regulated by lectin concentration.
