OBJECTIVE: To investigate the significance of Tim-3 and Galectin-9 in Th1/Th2 imbalance in patients with multiple myeloma (MM). METHODS: 55 newly diagnosed MM patients and 20 healthy controls were included. Flow cytometry was used to detect the expression of Tim-3 on CD4⁺T cells, the proportion of Th1, Th2, Tim-3⁺Th1 and Tim-3⁺Th2 cells in peripheral blood. ELISA was used to detect the levels of cytokines IFN-γ and IL-4 in serum, and PCR was used to detect the level of Galectin-9 mRNA. Then the correlations between Galectin-9 mRNA expression and Th-cell subsets and related cytokine levels, as well as the relationship between Tim-3⁺Th1/Tim-3⁺Th2 ratio and corresponding clinical features were analyzed. RESULTS: Compared with the control group, the expression of Tim-3 on CD4⁺T cells in peripheral blood of MM patients was significantly increased (P<0.05), the proportions of Tim-3⁺Th1 cells, Tim-3⁺Th2 cells and Tim-3⁺Th1/Tim-3⁺Th2 ratio in MM patients were also increased (P<0.05), while the proportion of Th1 cells and Th1/Th2 ratio in MM patients were significantly decreased (P<0.05). The level of cytokine IFN-γ and IFN-γ/IL-4 ratio in MM patients were significantly decreased (P<0.05), while the level of cytokine IL-4 was increased (P<0.05). The mRNA levels of Galectin-9 in MM patients were significantly increased (P<0.05). The levels of Galectin-9 mRNA were positively correlated with Tim-3⁺CD4⁺T cells (r=0.663), Tim-3⁺Th2 cells (r=0.492) and IL-4 (r=0.470), while negatively correlated with IFN-γ (r=-0.593). The ratios of Tim-3⁺Th1/Tim-3⁺Th2 in MM patients were positively correlated with ISS stage (r=0.511), osteolytic damage (r=0.556) and chromosome abnormality (r=0.632). CONCLUSION These results suggest that Tim-3 and Galectin-9 are involved in Th1/Th2 imbalance in MM patients, and the high ratio of Tim-3⁺Th1/Tim-3⁺Th2 is associated with poor clinical prognosis.
Humans ; Cytokines/metabolism* ; Galectins/metabolism* ; Hepatitis A Virus Cellular Receptor 2/metabolism* ; Interleukin-4/metabolism* ; Ligands ; Multiple Myeloma/metabolism* ; RNA, Messenger/metabolism* ; Th1 Cells/metabolism* ; Th2 Cells/metabolism*

The incidence of hematological malignant tumor is increasing year by year, and seriously affecting the human health. In addition to the traditional radiation and chemotherapy, immunotherapy has achieved a certain effect in the treatment of blood tumor, but it is limited by exhaustion of CD8
CD8-Positive T-Lymphocytes ; Galectins ; Hematologic Neoplasms ; Hepatitis A Virus Cellular Receptor 2 ; Humans ; Immunotherapy

Objective: To evaluate possible effects of Gelctin-9 on acute graft versus host disease (aGVHD) development and clinical outcomes in patients before and afer allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: Peripheral blood samples were obtained from 29 patients and 15 healthy volunteers with heparin anticoagulant tubes. Samples were analyzed using ELISA kits to measure the serum concentrations of Galectin-9. Results: Patients developing aGVHD had significantly lower level of Galectin-9 [ (7.96±1.18) μg/L] before allo-HSCT compared with those not developing aGVHD [ (12.37±0.97) μg/L, P<0.001]. And after allo-HSCT, the consentration of Galectin-9 increased markedly in patients developing aGVHD [ (17.78±1.78) μg/L] compared with those not developing aGVHD [ (9.45±0.80) μg/L, P<0.001]. Patients developing 3-4 grade aGVHD had significantly higher level of Galectin-9 [ (23.25±2.59) μg/L] compared with those developing 1-2 grade aGVHD [ (14.37±1.45) μg/L, P=0.008] and those without aGVHD [ (9.45±0.80) μg/L, P<0.001]. The patients with lower level of Galectin-9 after allo-HSCT (<13.61 μg/L) showed more favorable clinical outcomes compared with those with higher level of Galectin-9 (≥13.61 μg/L) . The 3-year overall survival rates were (100.00±6.05) % and (69.23±12.80) %, respectively (P=0.009) . The cumulative incidence of non-relapse mortality was significantly higher in high Galectin-9 group [ (23.08±11.69) %] in comparison with low Gaelctin-9 group [ (0.00±7.39) %] (P=0.023) . There was no significant difference between the two groups in terms of the cumulative incidence of relapse. The cumulative incidence of relapse at 3 years were (8.33±7.98) % and (12.50±8.27) % in high and low Galectin-9 groups, respectively (P=0.708) . Conclusions: The serum concentration of Galectin-9 at the time of engraftment after allo-HSCT may be used as a predictor for the development and severity of aGVHD. Galectin-9 might be considered as a potential new approach to regulate transplant rejection to achieve desirable survival.
Galectins ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Incidence ; Survival Rate ; Transplantation, Homologous

Galectin-4 (Gal-4) is a β-galactoside-binding protein mostly expressed in the gastrointestinal tract of animals. Although intensive functional studies have been done for other galectin isoforms, the immunoregulatory function of Gal-4 still remains ambiguous. Here, we demonstrated that Gal-4 could bind to CD14 on monocytes and induce their differentiation into macrophage-like cells through the MAPK signaling pathway. Gal-4 induced the phenotypic changes on monocytes by altering the expression of various surface molecules, and induced functional changes such as increased cytokine production and matrix metalloproteinase expression and reduced phagocytic capacity. Concomitant with these changes, Gal-4-treated monocytes became adherent and showed elongated morphology with higher expression of macrophage markers. Notably, we found that Gal-4 interacted with CD14 and activated the MAPK signaling cascade. Therefore, these findings suggest that Gal-4 may exert the immunoregulatory functions through the activation and differentiation of monocytes.
Animals ; Antigens, CD14 ; Cell Differentiation ; Galectin 4 ; Galectins ; Gastrointestinal Tract ; Macrophages ; Monocytes ; Protein Isoforms

BACKGROUND: The decidua has been implicated in the “terminal pathway” of human term parturition, which is characterized by the activation of pro-inflammatory pathways in gestational tissues. However, the transcriptomic changes in the decidua leading to terminal pathway activation have not been systematically explored. This study aimed to compare the decidual expression of developmental signaling and inflammation-related genes before and after spontaneous term labor in order to reveal their involvement in this process. METHODS: Chorioamniotic membranes were obtained from normal pregnant women who delivered at term with spontaneous labor (TIL, n = 14) or without labor (TNL, n = 15). Decidual cells were isolated from snap-frozen chorioamniotic membranes with laser microdissection. The expression of 46 genes involved in decidual development, sex steroid and prostaglandin signaling, as well as pro- and anti-inflammatory pathways, was analyzed using high-throughput quantitative real-time polymerase chain reaction (qRT-PCR). Chorioamniotic membrane sections were immunostained and then semi-quantified for five proteins, and immunoassays for three chemokines were performed on maternal plasma samples. RESULTS: The genes with the highest expression in the decidua at term gestation included insulin-like growth factor-binding protein 1 (IGFBP1), galectin-1 (LGALS1), and progestogen-associated endometrial protein (PAEP); the expression of estrogen receptor 1 (ESR1), homeobox A11 (HOXA11), interleukin 1β (IL1B), IL8, progesterone receptor membrane component 2 (PGRMC2), and prostaglandin E synthase (PTGES) was higher in TIL than in TNL cases; the expression of chemokine C-C motif ligand 2 (CCL2), CCL5, LGALS1, LGALS3, and PAEP was lower in TIL than in TNL cases; immunostaining confirmed qRT-PCR data for IL-8, CCL2, galectin-1, galectin-3, and PAEP; and no correlations between the decidual gene expression and the maternal plasma protein concentrations of CCL2, CCL5, and IL-8 were found. CONCLUSIONS: Our data suggests that with the initiation of parturition, the decidual expression of anti-inflammatory mediators decreases, while the expression of pro-inflammatory mediators and steroid receptors increases. This shift may affect downstream signaling pathways that can lead to parturition.
Chemokines ; Cytokines ; Decidua ; Estrogen Receptor alpha ; Estrogens ; Female ; Galectin 1 ; Galectin 3 ; Galectins ; Gene Expression* ; Genes, Homeobox ; Humans ; Immunoassay ; Interleukin-8 ; Interleukins ; Leukocytes ; Membranes ; Microdissection ; Parturition* ; Plasma ; Pregnancy ; Pregnant Women ; Progesterone ; Real-Time Polymerase Chain Reaction ; Receptors, Progesterone ; Receptors, Steroid ; Sexual Development ; Transcriptome*

Bone marrow-derived mesenchymal stem cells (MSCs) have immunomodulatory properties and can suppress exaggerated pro-inflammatory immune responses. Although the exact mechanisms remain unclear, a variety of soluble factors are known to contribute to MSC-mediated immunosuppression. However, functional redundancy in the immunosuppressive properties of MSCs indicates that other uncharacterized factors could be involved. Galectin-9, a member of the beta-galactoside binding galectin family, has emerged as an important regulator of innate and adaptive immunity. We examined whether galectin-9 contributes to MSC-mediated immunosuppression. Galectin-9 was strongly induced and secreted from human MSCs upon stimulation with pro-inflammatory cytokines. An in vitro immunosuppression assay using a knockdown approach revealed that galectin-9-deficient MSCs do not exert immunosuppressive activity. We also provided evidence that galectin-9 may contribute to MSC-mediated immunosuppression by binding to its receptor, TIM-3, expressed on activated lymphocytes, leading to apoptotic cell death of activated lymphocytes. Taken together, our findings demonstrate that galectin-9 is involved in MSC-mediated immunosuppression and represents a potential therapeutic factor for the treatment of inflammatory diseases.
Adaptive Immunity ; Apoptosis ; Cell Death ; Cytokines ; Galectins ; Humans* ; Immunosuppression* ; Lymphocytes ; Mesenchymal Stromal Cells*

Galectins are an evolutionarily ancient and widely expressed family of lectins that have unique glycan-binding characteristics. They are pleiotropic regulators of key biological processes, such as cell growth, proliferation, differentiation, apoptosis, signal transduction, and pre-mRNA splicing, as well as homo- and heterotypic cell-cell and cell-extracellular matrix interactions. Galectins are also pivotal in immune responses since they regulate host-pathogen interactions, innate and adaptive immune responses, acute and chronic inflammation, and immune tolerance. Some galectins are also central to the regulation of angiogenesis, cell migration and invasion. Expression and functional data provide convincing evidence that, due to these functions, galectins play key roles in shared and unique pathways of normal embryonic and placental development as well as oncodevelopmental processes in tumorigenesis. Therefore, galectins may sometimes act as double-edged swords since they have beneficial but also harmful effects for the organism. Recent advances facilitate the use of galectins as biomarkers in obstetrical syndromes and in various malignancies, and their therapeutic applications are also under investigation. This review provides a general overview of galectins and a focused review of this lectin subfamily in the context of inflammation, infection and tumors of the female reproductive tract as well as in normal pregnancies and those complicated by the great obstetrical syndromes.
Apoptosis ; Biomarkers ; Biological Processes ; Carcinogenesis ; Cell Movement ; Epigenomics ; Female ; Galectins* ; Host-Pathogen Interactions ; Humans ; Immune Tolerance ; Inflammation* ; Lectins ; Placentation ; Pregnancy ; Pregnancy Complications* ; RNA Precursors ; Signal Transduction

The relationship between T cell immunoglobulin domain and mucin domain protein 3 (Tim-3)/Galectin (Gal)-9 pathway and recurrent spontaneous abortion (RSA) was studied. Thirty-one pregnant women with RSA and 27 normal early gravidas were investigated to detect the levels of Tim-3 and Gal-9 in villi and deciduas by Western blotting. Meanwhile, the concentration of interleukin (IL)-4 and IL-12 in peripheral blood plasma was determined by ELISA in 25 healthy fertile non-pregnant controls, the normal early gravidas and pregnant women with RSA mentioned above, respectively. It was found that the relative expression levels of Tim-3 and Gal-9 in villi and deciduas were significantly increased in pregnant women with RSA as compared with those in the normal early gravidas. The concentration of IL-4 in peripheral blood plasma of pregnant women with RSA was lower than that of the normal early gravidas (P<0.05) and healthy fertile non-pregnant controls (P<0.05), but that of IL-2 in pregnant women with RSA was significantly higher than that of the normal early gravidas (P<0.05) and healthy fertile non-pregnant controls (P<0.05). It was suggested that the overexpression of Tim-3/Gal-9 pathway may be related to the pathogenesis of RSA.
Abortion, Spontaneous ; metabolism ; pathology ; Adolescent ; Adult ; Chorionic Villi ; metabolism ; pathology ; Female ; Galectins ; biosynthesis ; Hepatitis A Virus Cellular Receptor 2 ; Humans ; Interleukin-12 ; blood ; Interleukin-4 ; blood ; Membrane Proteins ; biosynthesis ; Pregnancy ; Pregnancy Proteins ; biosynthesis ; Up-Regulation

BACKGROUND AND OBJECTIVES: Existing data on the spatiotemporal expression patterns of a variety of galectins in murine atherosclerosis are limited. We investigated the expression levels of galectins, and their in vivo spatiotemporal expression patterns and statin responsiveness in the inflamed atherosclerotic plaques of apolipoprotein E (apoE)-/- mice. MATERIALS AND METHODS: Galectins expression patterns in aortic atherosclerotic plaques and serum galectin-3 levels were investigated in 26-week-old apoE-/- (n=6) and C57BL/6 mice (n=9). To investigate the spatial and temporal patterns of galectin-1 and galectin-3 in plaques, high-cholesterol diet-fed 26-week-old (n=12) and 36-week-old apoE-/- mice (n=6) were sacrificed and their aortas were examined for galectins' expression using immunoblot analysis and immunohistochemical stain. 36-week-old apoE-/- mice were treated with atorvastatin (n=3, 0.57 mg/kg/day) for the evaluation of its effect on aortic galectins' expression. RESULTS: Immunoblot analyses showed that galectin-1 and galectin-3 were the predominant galectins expressed in murine atherosclerosis. The serum galectin-3 level was significantly higher in apoE-/- mice (p<0.001). While galectin-1 was weakly expressed in both intimal plaques and the media of atherosclerotic aortas, galectin-3 was heavily and exclusively accumulated in intimal plaques. Galectin-3 distribution was colocalized with plaque macrophages' distribution (r=0.66). As the degree of plaque extent and inflammation increased, the intraplaque galectin-3 expression levels proportionally elevated (p<0.01 vs. baseline), whereas galectin-1 expression had not elevated (p=0.14 vs. baseline). Atorvastatin treatment markedly reduced intraplaque galectin-3 and macrophage signals (p<0.001 vs. baseline), whereas it failed to reduce galectin-1 expression in the aortas. CONCLUSION: Galectin-3 is the predominant gal and is colocalized with macrophages within atherosclerotic plaques. Intraplaque galectin-3 expression reflects the degree of plaque inflammation.
Animals ; Aorta ; Apolipoproteins ; Atherosclerosis ; Galectin 1 ; Galectin 3 ; Galectins ; Heptanoic Acids ; Inflammation ; Macrophages ; Mice ; Plaque, Atherosclerotic ; Pyrroles ; Atorvastatin Calcium

OBJECTIVE: To observe the correlation between the expression of galectin-7 and S100A9 with the development of cervical squamous carcinoma. METHODS: Immunohistochemical SP staining was used to detect the expression of galectin-7 and S100A9 in 243 patients with cervical intraepithelial neoplasia (CIN) or cervical squamous carcinoma. The association of clinical data with galectin-7 and S100A9 expression was examined. RESULTS: The expression of galectin-7 and S100A9 in CIN and cervical squamous carcinoma was significantly different (P<0.05). The positive rates of galectin-7 in normal cervical tissues, CIN I, CIN II, CIN III, and cervical squamous carcinoma were 56.7%, 41.9%, 32.0%, 27.3%, and 25.0%, respectively. Statistic analysis found significant difference between the normal cervical tissues and cervical squamous carcinoma (P<0.0045). The positive rates of S100A9 in CIN I, CIN II, CIN III, and cervical squamous carcinoma were 80.0%, 77.4%, 48.0%, 27.3%, and 20.2%. Statistic analysis showed significant difference between the normal tissues and CIN III, the normal cervical tissues and cervical squamous carcinoma, CIN I and CIN III, CIN I and cervical squamous carcinoma, CIN II and cervical squamous carcinoma (P<0.0045). A positive correlation was found between galectin-7 and S100A9 expression in CIN and cervical squamous carcinoma (rs=0.298, P<0.001). Expressions of both galectin-7 and S100A9 in cervical squamous carcinoma were associated with the clinical stage and lymph nodes (P<0.05), but not with patient's age and degree of differentiation (P>0.05). Expression of galectin-7 was associated with the survival rate of patients with cervical squamous carcinoma (P<0.05). Univariate analysis of Cox proportional hazards regression model revealed that the FIGO stage, lymph nodes metastasis, and the expression of galectin-7 were relevant to the 5 year survival rate of patients with cervical squamous carcinoma, which was confirmed by multiple analysis of Cox proportional hazards regression model. CONCLUSION Expression of galectin-7 and S100A9 is related with cervical the tumorigenesis of carcinoma, clinical stage, and lymph nodes of cervical squamous carcinoma. Galectin-7 is probably associated with the prognosis. The long-term survival of patients with cervical carcinoma may be associated with FIGO stage, lymph node metastasis, and the expression of galectin-7.
Calgranulin B ; metabolism ; Carcinoma, Squamous Cell ; metabolism ; Cell Differentiation ; Cervical Intraepithelial Neoplasia ; metabolism ; Female ; Galectins ; metabolism ; Humans ; Lymphatic Metastasis ; Prognosis ; Proportional Hazards Models ; Survival Rate ; Uterine Cervical Neoplasms ; metabolism