Regulated glycosylation controls T cell processes, including activation, differentiation and homing by creating or masking ligands for endogenous lectins. Here we show that stimuli promoting T helper type 1 (TH1), TH2 or interleukin 17-producing T helper (TH-17) differentiation can differentially regulate the glycosylation pattern of T helper cells and modulate their susceptibility to galectin-1, a glycan-binding protein with anti-inflammatory activity. Although TH1- and TH-17-differentiated cells expressed the repertoire of cell surface glycans critical for galectin-1-induced cell death, TH2 cells were protected from galectin-1 through differential sialylation of cell surface glycoproteins. Consistent with those findings, galectin-1-deficient mice developed greater TH1 and TH-17 responses and enhanced susceptibility to autoimmune neuroinflammation. Our findings identify a molecular link among differential glycosylation of T helper cells, susceptibility to cell death and termination of the inflammatory response.

The murine oct-3 gene encodes a transcription factor containing a POU-specific domain and a homeodomain. In marked contrast to other homeodomain-encoding genes, oct-3 is expressed in the totipotent and pluripotent stem cells of the pregastrulation embryo and is down-regulated during differentiation to endoderm and mesoderm, suggesting that it has a role in early development. The oct-3 gene is also expressed in primordial germ cells and in the female germ line.

Central to fibrogenesis and the scarring of organs is the activation of fibroblasts into matrix-secreting myofibroblasts. We demonstrate that Galectin-3 expression is up-regulated in established human fibrotic liver disease and is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis. Disruption of the Galectin-3 gene blocks myofibroblast activation and procollagen (I) expression in vitro and in vivo, markedly attenuating liver fibrosis. Addition of exogenous recombinant Galectin-3 in vitro reversed this abnormality. The reduction in hepatic fibrosis observed in the Galectin-3 ؊͞؊ mouse occurred despite equivalent liver injury and inflammation, and similar tissue expression of TGF-␤. TGF-␤ failed to transactivate Galectin-3 ؊͞؊ hepatic stellate cells, in contrast with WT hepatic stellate cells; however, TGF-␤-stimulated Smad-2 and -3 activation was equivalent. These data suggest that Galectin-3 is required for TGF-␤ mediated myofibroblast activation and matrix production. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation after hepatic injury and may therefore provide an alternative therapeutic approach to the prevention and treatment of liver fibrosis.hepatic stellate cell ͉ liver ͉ small interfering RNA ͉ TGF-␤

A successful pregnancy requires synchronized adaptation of maternal immune-endocrine mechanisms to the fetus. Here we show that galectin-1 (Gal-1), an immunoregulatory glycan-binding protein, has a pivotal role in conferring fetomaternal tolerance. Consistently with a marked decrease in Gal-1 expression during failing pregnancies, Gal-1-deficient (Lgals1-/-) mice showed higher rates of fetal loss compared to wild-type mice in allogeneic matings, whereas fetal survival was unaffected in syngeneic matings. Treatment with recombinant Gal-1 prevented fetal loss and restored tolerance through multiple mechanisms, including the induction of tolerogenic dendritic cells, which in turn promoted the expansion of interleukin-10 (IL-10)-secreting regulatory T cells in vivo. Accordingly, Gal-1's protective effects were abrogated in mice depleted of regulatory T cells or deficient in IL-10. In addition, we provide evidence for synergy between Gal-1 and progesterone in the maintenance of pregnancy. Thus, Gal-1 is a pivotal regulator of fetomaternal tolerance that has potential therapeutic implications in threatened pregnancies.

We describe that galectin-1 (gal-1) is a receptor for the angiogenesis inhibitor anginex, and that the protein is crucial for tumor angiogenesis. gal-1 is overexpressed in endothelial cells of different human tumors. Expression knockdown in cultured endothelial cells inhibits cell proliferation and migration. The importance of gal-1 in angiogenesis is illustrated in the zebrafish model, where expression knockdown results in impaired vascular guidance and growth of dysfunctional vessels. The role of gal-1 in tumor angiogenesis is demonstrated in gal-1-null mice, in which tumor growth is markedly impaired because of insufficient tumor angiogenesis. Furthermore, tumor growth in gal-1-null mice no longer responds to antiangiogenesis treatment by anginex. Thus, gal-1 regulates tumor angiogenesis and is a target for angiostatic cancer therapy.angiostatic therapy ͉ endothelial cell ͉ galectin ͉ tumor models ͉ anginex A n adequate vasculature is a prerequisite for tumors to grow, and the need for neovessel formation (or angiogenesis) provides a target for treatment of cancer (1). Endothelial cells (EC) that line the tumor vasculature are particularly suitable target cells for therapeutic approaches, because they are easily accessible to agents delivered by the blood (2). However, to affect only tumor vasculature, specific targets on angiogenically active EC are essential. To date, only a few targets of tumor vasculature have been identified (3).We recently developed the specific angiostatic peptide anginex, which inhibits tumor growth through specific inhibition of angiogenesis (4-6). Although a broad profile of activities of anginex is known, such as prevention of EC adhesion and induction of apoptosis, the molecular target on tumor EC was never identified. In a receptor-finding study using a yeast twohybrid screening approach, we identified galectin-1 (gal-1) as a target protein of anginex.gal-1 belongs to a family of carbohydrate-binding proteins that share a conserved carbohydrate recognition domain of Ϸ130 aa (7-9). Over a dozen mammalian galectins have been described (10, 11), and members of this family are expressed in a wide range of species, suggesting an important role for galectins in basic cellular mechanisms. Galectins can be secreted and, depending on the cell type or state of differentiation, they have been found in the nucleus, cytoplasm, or extracellular matrix. It has been proposed that gal-1 mediates cell adhesion and migration (12) and is involved in several processes, including proliferation (13), apoptosis (14), and even mRNA splicing (15). The role of gal-1 in EC function or vascular biology has not been extensively studied.Here, we describe the function of gal-1 in angiogenesis. We provide direct functional evidence that gal-1 is required for tumor angiogenesis and outgrowth of tumors. Furthermore, we show that gal-1 is the target for the potent angiogenesis inhibitor anginex, thus establishing gal-1 as an important target for anticancer therapy.Results gal-1 Binds the Angiostatic Peptide Anginex...