Chlamydophila psittaci-negative ocular adnexal marginal zone lymphomas express self polyreactive B-cell receptors.

The pathogenesis of Chlamydophila psittaci-negative ocular adnexal extranodal marginal zone lymphomas (OAEMZLs) is poorly understood. OAEMZLs are monoclonal tumors expressing a biased repertoire of mutated surface immunoglobulins. Antigenic activation of the B-cell receptor (BCR) may have a role in the pathogenesis of these lymphomas. We have analyzed the reactivity of recombinant OAEMZL immunoglobulins. OAEMZL antibodies reacted with self-human antigens, as demonstrated by enzyme-linked immunosorbent assays, HEp-2 immunofluorescence and human protein microarrays. All the analyzed recombinant antibodies (rAbs) exhibited polyreactivity by comprehensive protein array antibody reactivity and some rAbs also demonstrated rheumatoid factor activity. The identity of several reactive antigens was confirmed by microcapillary reverse-phase high-performance liquid chromatography nano-electrospray tandem mass spectrometry. The tested rAbs frequently reacted with shared intracellular and extracellular self-antigens (for example, galectin-3). Furthermore, these self-antigens induced BCR signaling in B cells expressing cognate surface immunoglobulins derived from OAEMZLs. These findings indicate that interactions between self-antigens and cognate OAEMZL tumor-derived BCRs are functional, inducing intracellular signaling. Overall, our findings suggest that self-antigen-induced BCR stimulation may be implicated in the pathogenesis of C. psittaci-negative OAEMZLs.

The bone marrow compartment is modified in the absence of galectin-3.

Galectin-3 (gal-3) is a ß-galactoside binding protein present in multivalent complexes with an extracellular matrix and with cell surface glycoconjugates. In this context, it can deliver a variety of intracellular signals to modulate cell activation, differentiation and survival. In the hematopoietic system, it was demonstrated that gal-3 is expressed in myeloid cells and surrounding stromal cells. Furthermore, exogenous and surface gal-3 drive the proliferation of myeloblasts in a granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent manner. Here, we investigated whether gal-3 regulates the formation of myeloid bone marrow compartments by studying galectin-3(-/-) mice (gal-3(-/-)) in the C57BL/6 background. The bone marrow histology of gal-3(-/-) mice was significantly modified and the myeloid compartments drastically disturbed, in comparison with wild-type (WT) animals. In the absence of gal-3, we found reduced cell density and diaphyseal disorders containing increased trabecular projections into the marrow cavity. Moreover, myeloid cells presented limited capacity to differentiate into mature myeloid cell populations in gal-3(-/-) mice and the number of hematopoietic multipotent progenitors was increased relative to WT animals. In addition, bone marrow stromal cells of these mice had reduced levels of GM-CSF gene expression. Taken together, our data suggest that gal-3 interferes with hematopoiesis, controlling both precursors and stromal cells and favors terminal differentiation of myeloid progenitors rather than proliferation.

Targeted disruption of the galectin-3 gene results in decreased susceptibility to multiple low dose streptozotocin-induced diabetes in mice.

Galectin 3 (Gal-3) is an antiapoptotic and a proinflammatory lectin. We hypothesized that the proinflammatory properties of Gal-3 may influence disease induction in the multiple low doses of streptozotocin model of diabetes. Diabetes was induced in C57BL/6 Gal-3(+/+) and Gal-3(-/-) mice and disease monitored by blood glucose level, immuno-histology, insulin content of islets and expression of the proinflammatory cytokines, TNF-alpha, IFN-gamma, IL-17, and iNOS in pancreatic lymph nodes. Gal-3(+/+) mice developed delayed and sustained hyperglycemia, mononuclear cellular infiltration and reduced insulin content of islets accompanied with expression of proinflammatory cytokines. Gal-3(-)/(-) mice were relatively resistant to diabetogenesis as evaluated by glycemia, quantitative histology and insulin content. Further, we observed the weaker expression of IFN-gamma and complete absence of TNF-alpha, and IL-17 in draining pancreatic lymph nodes. Macrophages, the first cells that infiltrate the islet in this model of diabetes, produce less TNF-alpha and NO in Gal-3(-/-) mice. Thus, Gal-3 is involved in immune mediated beta cell damage and is required for diabetogenesis in this model of disease.

Kinetics of mobilization and differentiation of lymphohematopoietic cells during experimental murine schistosomiasis in galectin-3 -/- mice.

Galectin-3 (gal-3), a beta-galactoside-binding animal lectin, plays a role in cell-cell and cell-extracellular matrix interactions. Extracellular gal-3 modulates cell migration and adhesion in several physiological and pathological processes. Gal-3 is highly expressed in activated macrophages. Schistosoma mansoni eggs display a large amount of gal-3 ligands on their surface and elicit a well-characterized, macrophage-dependent, granulomatous, inflammatory reaction. Here, we have investigated the acute and chronic phases of S. mansoni infection in wild-type and gal-3(-/-) mice. In the absence of gal-3, chronic-phase granulomas were smaller in diameter, displaying thinner collagen fibers with a loose orientation. Schistosoma-infected gal-3(-/-) mice had remarkable changes in the monocyte/macrophage, eosinophil, and B lymphocyte subpopulations as compared with the infected wild-type mice. We observed a reduction of macrophage number, an increase in eosinophil absolute number, and a decrease in B lymphocyte subpopulation (B220(+/high) cells) in the periphery during the evolution of the disease in gal-3(-/-) mice. B lymphopenia was followed by an increase of plasma cell number in bone marrow, spleen, and mesenteric lymph nodes of the infected gal-3(-/-) mice. The plasma IgG and IgE levels also increased in these mice. Gal-3 plays a role in the organization, collagen distribution, and mobilization of inflammatory cells to chronic-phase granulomas, niches for extramedullary myelopoiesis, besides interfering with monocyte-to-macrophage and B cell-to-plasma cell differentiation.

Functional capacity of macrophages determines the induction of type 1 diabetes.

Macrophages are potent immune regulators and are critical in the development and pathogenesis of autoimmune diabetes. They are said to be the first cell type to infiltrate the pancreatic islet, serve as antigen-presenting cells, and are important as effector cells during diabetogenesis. The article examines the role of macrophages in autoimmune diabetes with particular emphasis on the role of galectin-3, a beta-galactoside-binding lectin, and T1/ST2, an IL-1 receptor-like protein, both of which play significant roles in the immunomodulatory functions of macrophages. Multiple low-dose streptozotocin (MLD-STZ) induces infiltration of mononuclear cells in the islets of susceptible strains leading to insulitis. Deletion of the galectin-3 gene from C57BL/6 mice significantly attenuates this effect as evaluated by quantitative histology of mononuclear cells and loss of insulin-producing beta cells. In contrast, deletion of the ST2 gene enhanced insulitis after MLD-STZ treatment when compared with relatively resistant wild-type BALB/c mice. Thus, it appears that functional capacity of macrophages influences their participation in T helper (Th) 1-mediated autoimmunity and the development of autoimmune diabetogenesis.

Disrupted galectin-3 causes non-alcoholic fatty liver disease in male mice.

Galectin-3, a beta-galactoside-binding animal lectin, is a multifunctional protein. Previous studies have suggested that galectin-3 may play an important role in inflammatory responses. Non-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a liver condition that may progress to end-stage liver disease and based on the known functions of galectin-3, it was hypothesized that galectin-3 might play a role in the development of NAFLD. Thus, this study investigated the role of galectin-3 in NAFLD by comparing galectin-3 knockout (gal3(-/-)) mice and wild-type (gal3(+/+)) mice. The livers of gal3(-/-) male mice at 6 months of age histologically displayed mild to severe fatty change. The liver weight per body weight ratio, serum alanine aminotransferase levels, liver triglyceride levels, and liver lipid peroxide in gal3(-/-) mice were significantly increased compared with those in gal3(+/+) mice. Furthermore, the hepatic protein levels of advanced glycation end-products (AGE), receptor for AGE (RAGE), and peroxisome proliferator-activated receptor gamma (PPARgamma) were increased in gal3(-/-) mice relative to gal3(+/+) mice. In conclusion, this study suggests that the absence of gal3 can cause clinico-pathological features in male mice similar to those of NAFLD.

Polypeptide growth factors and phorbol ester induce progressive ankylosis (ank) gene expression in murine and human fibroblasts.

Polypeptide growth factors promote cellular proliferation by binding to specific plasma membrane-anchored receptors. This interaction triggers the phosphorylation of signal transducing molecules and the transcriptional activation of numerous genes. We have used a differential display approach to identify fibroblast growth factor (FGF)-1-inducible genes in murine NIH 3T3 fibroblasts. Here we report that one of these genes encodes ank, a type IIIa transmembrane protein reported to function in cells as an inorganic pyrophosphate transporter. FGF-1 induction of ank mRNA expression is first detectable at 2 h after growth factor addition and is dependent on de novo RNA and protein synthesis. Ank gene expression is also upregulated after treating quiescent fibroblasts with several other mitogenic agents (e.g., calf serum or platelet-derived growth factor-BB) or the tumor promoter phorbol 12-myristate 13-acetate. Furthermore, in comparison to parental NIH 3T3 cells, oncogene-transformed NIH 3T3 cells constitutively express elevated levels of ank mRNA. FGF-1 also increases ank gene expression in non-immortalized human embryonic lung fibroblasts. Finally, the murine and human ank genes are expressed in vivo in a tissue-specific manner, with highest levels of mRNA expression found in brain, heart, and skeletal muscle. These results indicate that ank is a growth factor-regulated delayed-early response gene in mammalian cells, and we propose that increased ank expression during cell cycle progression may be necessary to maintain proper intracellular pyrophosphate levels during conditions of high cellular metabolic activity.

Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice.

Several molecules were shown to bind advanced glycation end products (AGEs) in vitro, but it is not known whether they all serve as AGE receptors and which functional role they play in vivo. We investigated the role of galectin-3, a multifunctional lectin with (anti)adhesive and growth-regulating properties, as an AGE receptor and its contribution to the development of diabetic glomerular disease, using a knockout mouse model. Galectin-3 knockout mice obtained by gene ablation and the corresponding wild-type mice were rendered diabetic with streptozotocin and killed 4 months later, together with age-matched nondiabetic controls. Despite a comparable degree of metabolic derangement, galectin-3-deficient mice developed accelerated glomerulopathy vs. the wild-type animals, as evidenced by the more pronounced increase in proteinuria, extracellular matrix gene expression, and mesangial expansion. This was associated with a more marked renal/glomerular AGE accumulation, indicating it was attributable to the lack of galectin-3 AGE receptor function. The galectin-3-deficient genotype was associated with reduced expression of receptors implicated in AGE removal (macrophage scavenger receptor A and AGE-R1) and increased expression of those mediating cell activation (RAGE and AGE-R2). These results show that the galectin-3-regulated AGE receptor pathway is operating in vivo and protects toward AGE-induced tissue injury in contrast to that through RAGE.

Cell cycle regulation by galectin-12, a new member of the galectin superfamily.

Galectins are a family of beta-galactoside-binding animal lectins with conserved carbohydrate recognition domains (CRDs). Here we report the identification and characterization of a new galectin, galectin-12, which contains two domains that are homologous to the galectin CRD. The N-terminal domain contains all of the sequence elements predicted to form the two beta-sheets found in other galectins, as well as conserved carbohydrate-interacting residues. The C-terminal domain shows considerable divergence from the consensus sequence, and many of these conserved residues are not present. Nevertheless, the protein has lactose binding activity, most likely due to the contribution of the N-terminal domain. The mRNA for galectin-12 contains features coding for proteins with growth-regulatory functions. These include start codons in a context that are suboptimal for translation initiation and AU-rich motifs in the 3'-untranslated region, which are known to confer instability to mRNA. Galectin-12 mRNA is sparingly expressed or undetectable in many tissues and cell lines tested, but it is up-regulated in cells synchronized at the G(1) phase or the G(1)/S boundary of the cell cycle. Ectopic expression of galectin-12 in cancer cells causes cell cycle arrest at the G(1) phase and cell growth suppression. We conclude that galectin-12 is a novel regulator of cellular homeostasis.

Human galectin-3 is a novel chemoattractant for monocytes and macrophages.

Galectin-3 is a beta-galactoside-binding protein implicated in diverse biological processes. We found that galectin-3 induced human monocyte migration in vitro in a dose-dependent manner, and it was chemotactic at high concentrations (1.0 microM) but chemokinetic at low concentrations (10-100 nM). Galectin-3-induced monocyte migration was inhibited by its specific mAb and was blocked by lactose and a C-terminal domain fragment of the protein, indicating that both the N-terminal and C-terminal domains of galectin-3 are involved in this activity. Pertussis toxin (PTX) almost completely blocked monocyte migration induced by high concentrations of galectin-3. Galectin-3 caused a Ca2+ influx in monocytes at high, but not low, concentrations, and both lactose and PTX inhibited this response. There was no cross-desensitization between galectin-3 and any of the monocyte-reactive chemokines examined, including monocyte chemotactic protein-1, macrophage inflammatory protein-1alpha, and stromal cell-derived factor-1alpha. Cultured human macrophages and alveolar macrophages also migrated toward galectin-3, but not monocyte chemotactic protein-1. Finally, galectin-3 was found to cause monocyte accumulation in vivo in mouse air pouches. These results indicate that galectin-3 is a novel chemoattractant for monocytes and macrophages and suggest that the effect is mediated at least in part through a PTX-sensitive (G protein-coupled) pathway.

Targeted disruption of the galectin-3 gene results in attenuated peritoneal inflammatory responses.

Galectin-3 is a member of a growing family of beta-galactoside-binding animal lectins. Previous studies have demonstrated a variety of biological activities for this protein in vitro, including activation of cells, modulation of cell adhesion, induction of pre-mRNA splicing, and regulation of apoptosis. To assist in fully elucidating the physiological and pathological functions of this protein, we have generated galectin-3-deficient (gal3(-/-)) mice by targeted interruption of the galectin-3 gene. Gal3(-/-) mice consistently developed fewer inflammatory cell infiltrations in the peritoneal cavities than the wild-type (gal3(+/+)) mice in response to thioglycollate broth treatment, mainly due to lower numbers of macrophages. Also, when compared to cells from gal3(+/+) mice, thioglycollate-elicited inflammatory cells from gal3(-/-) mice exhibited significantly lower levels of NF-kappaB response. In addition, dramatically different cell-spreading phenotypes were observed in cultured macrophages from the two genotypes. Whereas macrophages from gal3(+/+) mice exhibited well spread out morphology, those from gal3(-/-) mice were often spindle-shaped. Finally, we found that peritoneal macrophages from gal3(-/-) mice were more prone to undergo apoptosis than those from gal3(+/+) mice when treated with apoptotic stimuli, suggesting that expression of galectin-3 in inflammatory cells may lead to longer cell survival, thus prolonging inflammation. These results strongly support galectin-3 as a positive regulator of inflammatory responses in the peritoneal cavity.

The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration.

The binding of polypeptide growth factors to their appropriate cell surface transmembrane receptors triggers numerous biochemical responses, including the transcriptional activation of specific genes. We have used a differential display approach to identify fibroblast growth factor-1-inducible genes in murine NIH 3T3 cells. Here, we report that the fibroblast growth factor-inducible-14 (Fn14) gene is a growth factor-regulated, immediate-early response gene expressed in a developmental stage- and adult tissue-specific manner in vivo. This gene, located on mouse chromosome 17, is predicted to encode an 129-amino acid type Ia membrane protein with no significant sequence similarity to any known protein. We have used two experimental approaches, direct fluorescence microscopy and immunoprecipitation analysis of biotinylated cell surface proteins, to demonstrate that Fn14 is located on the plasma membrane. To examine the biological consequences of constitutive Fn14 expression, we isolated NIH 3T3 cell lines expressing variable levels of epitope-tagged Fn14 and analyzed their phenotypic properties in vitro. These experiments revealed that Fn14 expression decreased cellular adhesion to the extracellular matrix proteins fibronectin and vitronectin and also reduced serum-stimulated cell growth and migration. These results indicate that Fn14 is a novel plasma membrane-spanning molecule that may play a role in cell-matrix interactions.

Galectin-3 expression is induced in cirrhotic liver and hepatocellular carcinoma.

Galectins are a family of beta-galactoside-binding animal lectins. In particular, a widely studied member galectin-3, previously designated as epsilonBP, CBP35, Mac-2, L-29 and L-34, has been associated with assorted processes such as cell growth, tumor transformation and metastasis. Galectin-3 is expressed in various tissues and organs but is significantly absent in normal hepatocytes. However, evaluation of patient liver biopsies for galectin-3 expression resulted in the finding that hepatocellular carcinoma (HCC) frequently expressed significant levels of this lectin (76% immunohistochemically positive). Further investigation revealed that galectin-3 expression in HCC is independent of whether the patient had prior hepatitis B virus infection: 14 of 18 HCC cases from HBV- patients, and 5 of 7 cases from HBV patients demonstrated positive galectin-3 immunohistochemistry. However, co-transfection studies using a galectin-3 promoter construct and an HBV-X protein (HBV-X) expression vector demonstrated that galectin-3 expression can occur through transactivation of the lectin promoter by HBV-X. Based on presently known properties of this lectin, it is possible that deregulated expression of galectin-3 can result in tumor transformation and invasiveness, or confer propensity for tumor cell survival. In addition, galectin-3 was abundantly expressed in cirrhotic liver in peripheral distribution within regenerating nodules. Such galectin-3 expression in rapidly proliferating hepatocytes in cirrhotic liver may be a result of the high mitotic index. Alternatively, it is possible that proliferating cells expressing galectin-3 are in the process of being transformed, thus indicating an early neoplastic event.

Role of the carboxyl-terminal lectin domain in self-association of galectin-3.

Galectin-3 is a member of a large family of beta-galactoside-binding animal lectins and is composed of a carboxyl-terminal lectin domain connected to an amino-terminal nonlectin part. Previous experimental results suggest that, when bound to multivalent glycoconjugates, galectin-3 self-associates through intermolecular interactions involving the amino-terminal domain. In this study, we obtained evidence suggesting that the protein self-associates in the absence of its saccharide ligands, in a manner that is dependent on the carboxyl-terminal domain. This mode of self-association is inhibitable by the lectin's saccharide ligands. Specifically, recombinant human galectin-3 was found to bind to galectin-3C (the carboxyl-terminal domain fragment) conjugated to Sepharose 4B and the binding was inhibitable by lactose. In addition, biotinylated galectin-3 bound to galectin-3 immobilized on plastic surfaces and the binding could also be inhibited by various saccharide ligands of the lectin. A mutant with a tryptophan to leucine replacement in the carboxyl-terminal domain, which exhibited diminished carbohydrate-binding activity, did not bind to galectin-3C-Sepharose 4B. Furthermore, galectin-3C formed covalent homodimers when it was treated with a chemical cross-linker and the dimer formation was completely inhibited by lactose. Therefore, galectin-3 can self-associate through intermolecular interactions involving both the amino- and the carboxyl-terminal domains and the relative contribution of each depends on whether the lectin is bound to its saccharide ligands.

Fibroblast growth factor-1 induction of delayed-early mRNA expression in NIH 3T3 cells is prolonged by heparin addition.

Fibroblast growth factor (FGF)-1, also known as acidic FGF, is a multifunctional heparin-binding protein that is mitogenic for a wide variety of cell types cultured in vitro and a potent angiogenic agent in vivo. These cellular responses are mediated via high-affinity binding to a family of four membrane-spanning tyrosine kinase receptors. FGF-1-stimulated mitogenesis is potentiated by heparin, a sulfated glycosaminoglycan. In this study, we examined the effect of exogenous heparin on FGF-1-inducible gene expression in murine NIH 3T3 cells using both wild-type FGF-1 and FGF-1/glu132, an FGF-1 mutant with a reduced apparent affinity for heparin. The induction levels and temporal expression kinetics of two immediate-early response mRNAs (early growth response gene-1, thrombospondin-1) as well as two delayed-early response mRNAs (proliferin, ornithine decarboxylase) were monitored by Northern blot hybridization analysis. We found that although FGF-1 alone can promote the initial induction of these four mRNAs, heparin coaddition is necessary for prolonged delayed-early mRNA expression. This heparin effect occurs when cells are stimulated with wild-type FGF-1 but not with FGF-1/glu132. Furthermore, FGF-1 and heparin must be added together at the initial time of mitogen stimulation and they must remain present in the cell culture medium for a minimum period of 8 h to promote sustained delayed-early mRNA expression. These findings are consistent with the proposal that heparin promotes a long-term FGF-1:FGFR interaction which is required for sustained delayed-early gene expression and a full mitogenic response.

Differential control of murine aldose reductase and fibroblast growth factor (FGF)-regulated-1 gene expression in NIH 3T3 cells by FGF-1 treatment and hyperosmotic stress.

Aldose reductase (AR) is an NADPH-dependent aldo-keto reductase implicated in cellular osmoregulation and detoxification. Two distinct murine genes have been identified that are predicted to encode proteins with significant amino acid sequence identity with mouse AR: mouse vas deferens protein and fibroblast growth factor (FGF)-regulated-1 protein (FR-1). Here we report that the AR and FR-1 genes are differentially regulated in NIH 3T3 fibroblasts. FGF-1 stimulation of quiescent cells induces both AR and FR-1 mRNA levels, but the effect on FR-1 mRNA expression is significantly greater. FGF-1 treatment also increases FR-1 protein expression, as determined by Western-blot analysis using FR-1-specific polyclonal antiserum. Calf serum stimulation of quiescent cells increases AR mRNA expression but not FR-1 mRNA expression. Finally, when NIH 3T3 cells are grown in hypertonic medium, AR mRNA levels are significantly increased whereas FR-1 mRNA levels are only slightly up-regulated. These results indicate that the AR and FR-1 genes are differentially regulated in murine fibroblasts by two different growth-promoting agents and by hyperosmotic stress. Therefore these structurally related enzymes may have at least some distinct cellular functions; for example, although both AR and FR-1 activity may be important for the metabolic changes associated with cellular proliferation, AR may be the primary aldo-keto reductase involved in cellular osmoregulation.

Fibroblast growth factor-1 stimulation of quiescent NIH 3T3 cells increases G/T mismatch-binding protein expression.

Polypeptide growth factors promote cell-cycle progression in part by the transcriptional activation of a diverse group of specific genes. We have used an mRNA differential-display approach to identify several fibroblast growth factor (FGF)-1 (acidic FGF)-inducible genes in NIH 3T3 cells. Here we report that one of these genes, called FGF-regulated (FR)-3, is predicted to encode G/T mismatch-binding protein (GTBP), a component of the mammalian DNA mismatch correction system. The murine GTBP gene is transiently expressed after FGF-1 or calf serum treatment, with maximal mRNA levels detected at 12 and 18 h post-stimulation. FGF-1-stimulated NIH 3T3 cells also express an increased amount of GTBP as determined by immunoblot analysis. These results indicate that elevated levels of GTBP may be required during the DNA synthesis phase of the cell cycle for efficient G/T mismatch recognition and repair.

Heparin-binding epidermal growth factor-like growth factor regulates fibroblast growth factor-2 expression in aortic smooth muscle cells.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a vascular smooth muscle cell (SMC) mitogen and chemotactic factor that is expressed by endothelial cells, SMCs, monocytes/macrophages, and T lymphocytes. Both the membrane-anchored HB-EGF precursor and the secreted mature HB-EGF protein are biologically active; thus, HB-EGF may stimulate SMC growth via autocrine, paracrine, and juxtacrine mechanisms. In the present study, we report that HB-EGF treatment of serum-starved at aortic SMCs can induce fibroblast growth factor (FGF)-2 (basic FGF) gene expression but not FGF-1 (acidic FGF) gene expression. Increased FGF-2 mRNA expression is first detectable at 1 hour after HB-EGF addition, and maximal FGF-2 mRNA levels, corresponding to an approximately 46-fold level of induction, are present at 4 hours. The effect of HB-EGF on FGF-2 mRNA levels appears to be mediated primarily by a transcriptional mechanism and requires de novo synthesized proteins. HB-EGF induction of FGF-2 mRNA levels can be inhibited by treating cells with the anti-inflammatory glucocorticoid dexamethasone or the glycosaminoglycan heparin. Finally, Western blot analyses indicate that HB-EGF-treated SMCs also produce an increased amount of FGF-2 protein. These results indicate that HB-EGF expressed at sites of vascular injury or inflammation in vivo may upregulate FGF-2 production by SMCs.

Expression of galectin-3 modulates T-cell growth and apoptosis.

Galectin-3 is a member (if a large family of beta-galactoside-binding animal lectins. It has been shown that the expression of galectin-3 is upregulated in proliferating cells, suggesting a possible role for this lectin in regulation of cell growth. Previously, we have shown that T cells infected with human T-cell leukemia virus type I express high levels of galectin-3, in contrast to uninfected cells, which do not express detectable amounts of this protein. In this study, we examined growth properties of human leukemia T cells transfected with galectin-3 cDNA, and thus constitutively overexpressing this lectin. Transfectants expressing galectin-3 displayed higher growth rates than control transfectants, which do not express this lectin. Furthermore, galectin-3 expression in these cells confers resistance to apoptosis induced by anti-Fas antibody and staurosporine. Galectin-3 was found to have significant sequence similarity with Bcl-2, a well-characterized suppressor of apoptosis. In particular, the lectin contains the NWGR motif that is highly conserved among members of the Bcl-2 family and shown to be critical for the apoptosis-suppressing activity. We further demonstrated that galectin-3 interacts with Bc1-2 in a lactose-inhibitable manner. We conclude that galectin-3 is a regulator of cell growth and apoptosis and it may function through a cell death inhibition pathway that involves Bcl-2.