• Journal of Ginseng Research
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• v.36 no.4
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• pp.375-382
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• 2012

Ginsenoside Rp1 (G-Rp1) is a saponin derivate that provides anti-metastatic activities through inhibition of the NF-${\kappa}B$ pathway. In this study, we examined the effects of G-Rp1 on regulatory T cell (Treg) activation. After treatment of splenocytes with G-Rp1, Tregs exhibited upregulation of IL-10 expression, and along with dendritic cells (DCs), these Tregs showed increased cell number compared to other cell populations. The effect of G-Rp1 on Treg number was augmented in the presence of lipopolysaccharide (LPS), which mimics pathological changes that occur during inflammation. However, depletion of DCs prevented the increase in Treg number in the presence of G-Rp1 and/or LPS. In addition, G-Rp1 promoted the differentiation of the memory types of $CD4^+Foxp3^+CD62L^{low}$ Tregs rather than the generation of new Tregs. In vivo experiments also demonstrated that Tregs and DCs from mice that were fed G-Rp1 for 7 d and then injected with LPS exhibited increased activation compared with those from mice that were injected with LPS alone. Expression of TGF-${\beta}$ and CTLA4 in Tregs was increased, and upregulation of IL-2 and CD80/CD86 expression by DCs affected the suppressive function of Tregs through IL-2 receptors and CTLA4. These data demonstrate that G-Rp1 exerts anti-inflammatory effects by activating Tregs in vitro and in vivo.

• Journal of Ginseng Research
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• v.42 no.4
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• pp.447-454
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• 2018

Background: Korean ginseng has been widely evaluated to treat human diseases; however, most studies on Korean ginseng have focused on its root. In this study, polysaccharides [acidic-polysaccharide-linked glycopeptide (APGP) extracted with 90% ethanol and hot water] were prepared from Korean ginseng berries, and their effect on immunosenescence was explored. Methods: The effect of APGP on thymic involution was evaluated by measuring the size of thymi dissected from aged mice. The effect of APGP on populations of immune cells, including natural killer (NK) cells, dendritic cells, age-correlated CD11c-positive B cells, and several subtypes of T cells [CD4-positive, CD8-positive, and regulatory (Treg) T cells] in the thymi and spleens of aged mice was analyzed by fluorescence-activated cell sorting analysis. Serum levels of interleukin (IL)-2 and IL-6 were evaluated by enzyme-linked immunosorbent assay analysis. Profiles of APGP components were evaluated by high-performance liquid chromatography (HPLC) analysis. Results: APGP suppressed thymic involution by increasing the weight and areas of thymi in aged mice. APGP increased the population of NK cells, but showed no effect on the population of dendritic cells in the thymi and spleens of aged mice. APGP decreased the population of age-correlated CD11c-positive B cells in the spleens of aged mice. APGP showed no effect on the populations of CD4- and CD8-positive T cells in the thymi of aged mice, whereas it increased the population of Treg cells in the spleens of aged mice. APGP further decreased the reduced serum levels of IL-2 in aged mice, but serum levels of IL-6 were not statistically changed by APGP in aged mice. Finally, HPLC analysis showed that APGP had one major peak at 15 min (a main type of polysaccharide) and a long tail up to 35 min (a mixture of a variety of types of polysaccharides). Conclusion: These results suggested that APGP exerted an anti-immunosenescent effect by suppressing thymic involution and modulating several types of immune cells.

• IMMUNE NETWORK
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• v.23 no.6
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• pp.48.1-48.21
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• 2023

Mesenchymal stromal/stem cells (MSCs) possess immunoregulatory properties and their regulatory functions represent a potential therapy for acute lung injury (ALI). However, uncertainties remain with respect to defining MSCs-derived immunomodulatory pathways. Therefore, this study aimed to investigate the mechanism underlying the enhanced effect of human recombinant bone morphogenic protein-2 (rhBMP-2) primed ES-MSCs (MSC^BMP2) in promoting Tregs in ALI mice. MSC were preconditioned with 100 ng/ml rhBMP-2 for 24 h, and then administrated to mice by intravenous injection after intratracheal injection of 1 mg/kg LPS. Treating MSCs with rhBMP-2 significantly increased cellular proliferation and migration, and cytokines array reveled that cytokines release by MSC^BMP2 were associated with migration and growth. MSC^BMP2 ameliorated LPS induced lung injury and reduced myeloperoxidase activity and permeability in mice exposed to LPS. Levels of inducible nitric oxide synthase were decreased while levels of total glutathione and superoxide dismutase activity were further increased via inhibition of phosphorylated STAT1 in ALI mice treated with MSC^BMP2. MSC^BMP2 treatment increased the protein level of IDO1, indicating an increase in Treg cells, and Foxp3⁺CD25⁺ Treg of CD4⁺ cells were further increased in ALI mice treated with MSC^BMP2. In co-culture assays with MSCs and RAW264.7 cells, the protein level of IDO1 was further induced in MSC^BMP2. Additionally, cytokine release of IL-10 was enhanced while both IL-6 and TNF-α were further inhibited. In conclusion, these findings suggest that MSC^BMP2 has therapeutic potential to reduce massive inflammation of respiratory diseases by promoting Treg cells.

• The Korea Journal of Herbology
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• v.24 no.1
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• pp.73-78
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• 2009

Objectives : In this study, we studied the effect of Pinellia Ternata (PT) on regulatory T cells and CD3+CCR3+ Th2 cells number in asthma model mice. Methods : All mice were immunized on two different days (21 days and 7 days before inhalational exposure) by i.p. injections of 0.2 $m\ell$ alum-precipitated Ag containing 100 ${\mu}g$ of OVA bound to 4 mg of aluminum hydroxide in PBS. Seven days after the second sensitization, mice were exposed to aerosolized ovalbumin for 30 min/day on 3 days/week for 12 weeks(at a flow rate of 250 L/min, 2.5％ ovalbumin in normal saline) and PT (400, 200 mg/kg) were orally administered 3 times a week for 8 weeks. After C57BL/6 mice were orally given of PT, the percentages, cell numbers, phenotype and function of CD4+CD25+Treg cells were determined by flow cytometry. Results : The cell numbers of CD4+CD25+Treg cell subsets were markedly increased in PT treated mice as reported. However, PT significantly reduced the CD3+CCR3+ Th2 cells in PBMC and lung of mice. Conclusions : These results indicate that PT has a deep inhibitory effect on asthma model mice by increase the number of regulatory T cells, and by reducing CD3+CCR3+ Th2 cells.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.13
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• pp.5181-5186
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• 2014

Tumors have evolved numerous mechanisms by which they can escape from immune surveillance. One of these is to produce immunosuppressive cytokines. Transforming growth factor-${\beta}$(TGF-${\beta}$) is a pleiotropic cytokine with a crucial function in mediating immune suppression, especially in the tumor microenvironment. TGF-${\beta}$ produced by T cells has been demonstrated as an important factor for suppressing antitumor immune responses, but the role of tumor-derived TGF-${\beta}$ in this process is poorly understood. In this study, we demonstrated that knockdown of tumor-derived TGF-${\beta}$ using shRNA resulted in dramatically reduced tumor size, slowing tumor formation, prolonging survival rate of tumor-bearing mice and inhibiting metastasis. We revealed possible underlying mechanisms as reducing the number of myeloid-derived suppressor cells (MDSC) and $CD4^+Foxp3^+$ Treg cells, and consequently enhanced IFN-${\gamma}$ production by CTLs. Knockdown of tumor-derived TGF-${\beta}$ also significantly reduced the conversion of na$\ddot{i}$ve $CD4^+$ T cells into Treg cells in vitro. Finally, we found that knockdown of TGF-${\beta}$ suppressed cell migration, but did not change the proliferation and apoptosis of tumor cells in vitro. In summary, our study provided evidence that tumor-derived TGF-${\beta}$ is a critical factor for tumor progression and evasion of immune surveillance, and blocking tumor-derived TGF-${\beta}$ may serve as a potential therapeutic approach for cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3077-3084
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• 2016

Various beneficial effects have been described for fermented papaya preparation (FPP: SAIDO-PS501) based on its anti-oxidative and anti-inflammatory functions. The present study was designed to determine the effects of FPP on carcinogenesis in vivo, and immunomodulatory function in vitro. Mice were injected with RL male 1 cells subcutaneously or 3-methylcholantherene (MCA) intravenously to induce cancer and orally or intraperitoneally treated with FPP solution. Human peripheral blood mononuclear cells (PBMC) were obtained from healthy volunteers and patients with atopic dermatitis, treated with FPP, and subjected to measurement of cytokine production and changes in Foxp3-expressing regulatory T cell (Treg) stimulated with phytohemagglutinin (PHA). Administration of FPP suppressed tumor size and the incidence of malignancy. In vitro, treatment of PBMC with FPP induced IL-$1{\beta}$, $TNF{\alpha}$ and $IFN{\gamma}$ production. Moreover, FPP suppressed proliferation of PHA-stimulated Foxp3-expressing Treg. These results suggest that FPP has chemotherapeutic properties.

• BLOOD RESEARCH
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• v.53 no.4
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• pp.294-298
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• 2018

Background Production of immunosuppressive enzymes such as indoleamine 2,3-dioxygenase (IDO) is one of the strategies employed by hematologic malignancies, including acute myeloid leukemia (AML), to circumvent immune surveillance. Moreover, IDO has the ability to convert $CD4^+CD25^-$ conventional T cells into regulatory T cells (Tregs). In this study, we evaluated the expression of IDO in cytogenetically normal acute myeloid leukemia (CN-AML) patients and its correlation with the Treg marker, FOXP3, as well as clinical and laboratory parameters. Methods Thirty-seven newly diagnosed CN-AML patients were enrolled in our study along with 22 healthy individuals. The expression of the IDO and FOXP3 genes was analyzed by SYBR Green real-time PCR. Results Both IDO and FOXP3 were highly upregulated in CN-AML patients compared to control groups (P=0.004 and P=0.031, respectively). A positive correlation was observed between IDO and FOXP3 expression among AML patients (r=0.512, P=0.001). Expression of IDO and FOXP3 showed no significant correlation with laboratory parameters such as white blood cell and platelet counts, hemoglobin levels, bone marrow blast percentage, gender, and FLT3 mutation status (P>0.05). Conclusion Higher IDO expression in CN-AML patients may be associated with an increased Treg phenotype which may promote disease progression and lead to poor prognosis of CN-AML patients.

• Microbiology and Biotechnology Letters
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• v.37 no.2
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• pp.160-169
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• 2009

Poly-$\gamma$-glutamic acid ($\gamma$-PGA) was mixed natural flora of Bacillus subtilis, contaminated from cooked soybeans. Also, it was performed to find out the antiallergic activity by using NC/Nga mice, in vitro. The $\gamma$-PGA (PGA-HM : PGA-high molecular weight), Molecular weight 300 kDa, was decomposed and made PGA-LM (PGA-low molecular weight) which has molecular weight below 30 kDa by sonication. Therefore, it was same result between PGA-HM and PGA-LM, and reported PGA-LM as basic result. We found that PGA-LM contains antiallergic efficacy that inhibit B cells and Th2 cells activation from isolated CD4+T cells in NC/Nga atopic dermatitis model mice, and not show a cytotoxicity in the hFCs. To investigate the effects of these PGA-LM in vitro, isolation of splenic B cell and CD4+ T cells in atopic dermatitis mice were used. To elucidate the role of PGA-LM in anti-CD40+ interleukin-4 (IL-4)-mediated B-cell activation, showed that the capacity of B cells to expression IL-$1\beta$, IL-6, and TNF-$\alpha$ mRNA down-regulated, and IL-10 mRNA up-regulation by PGA-LM treatment, but it had no effect on TGF-$\beta$ expression. In addition to CD4+IFN-$\gamma$+ and CD4+CD25+foxp3+, the functions of PGA-LM in the development of the CD4+CD25+foxp3+ and CD4+IFN-$\gamma$+cells, the phenotype and functions of PGA-LM induced CD4+CD25+foxp3+, and CD4+IFN-$\gamma$+cells in CD4+T cells. These results suggested that PGA-LM could change cytokine production and generate CD4+CD25+foxp3+ Tregs in NC/Nga mice, and may be effective for immunotherapy in patients with AD.

• Journal of Microbiology and Biotechnology
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• v.25 no.10
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• pp.1687-1696
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• 2015

Supplementation with probiotics can protect against the development of food allergies by modulating the host immune response; however, the mechanisms are not fully understood. The objective of this study was to investigate the allergy-reducing effects of regulatory dendritic cells (regDCs) induced by Lactobacillus paracasei L9 (L9) in β-lactoglobulin (BLG)-sensitized mice. The L9 supplement suppressed the aberrant balance of Th1/Th2 responses to BLG in mice, via upregulation of the CD4+CD25+Foxp3+Treg cell responses. The amount of CD4+CD25+Foxp3+Treg cells in mesenteric lymph nodes increased by 51.85%. Furthermore, administration of L9 significantly induced the expression of CD103 and reduced the maturation status of DCs in mesenteric lymph nodes, Peyer's patches, and spleen. Bone marrow-derived dendritic cells (BM-DCs) were activated by L9 in vitro, with an approximate 1.31-fold and 19.57-fold increase in expression of CD103 in CD11c+DCs and the level of IL-10 production, respectively, while the expression of CD86 did not change significantly. These data demonstrate that L9 reduced the BLG allergic sensitization, likely through regDCs mediated active suppression.

• Journal of Physiology & Pathology in Korean Medicine
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• v.25 no.3
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• pp.459-465
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• 2011

The nuclear factor of activated T cells (NFAT) protein induces transcriptions of cytokine genes including IL-2 for T-cell activation. Normally activation of NFAT is important to induce immune responses but excessive NFAT activation provokes immunopathological reactions such as autoimmunity, transplant rejection, and inflammation. Thus, for the treatment of autoimmune diseases drugs repressing the activation of NFAT have been searched. In this study, immnunosuppressive effects of Rosa chinensis Jacq. extracts identified as a potent NFAT inhibitor from a natural product library were examined. NFAT reporter assay, MTS assay, real time PCR, IL-2 ELISA, MLR, and FACS (Fluorescent Activated Cell Sorting) were used to measure inhibitory immunocyte activities of Rosa chinensis Jacq. The variety of natural products have been screened and some were found to show inhibitory activities against the NFAT transcription factor. Among them, extract of Rosa chinensis Jacq. showed an strong inhibitory effect on the activation of NFAT without affecting cell viability. Levels of IL-2 transcripts as well as IL-2 protein were decreased with treatment of Rosa chinensis Jacq. extract. In addition, immunosuppressive activity of Rosa chinensis Jacq. extract was exhibited in the mixed leukocytes reaction. The increasement of CD4+CD25+ (Treg) immunocyte was also detected in the analysis using FACS after applying Rosa chinensis Jacq. extract. Immunosuppressive effects of the Rosa chinensis Jacq. extracts were clearly demonstrated in the present study. In addition, Rosa chinensis Jacq. extract also positively affected regulatory T cell induction. Further investigations in particular on purification of single substance responsible for the immunosuppressive effects from the extract and analysis on possible actions of the extract in interfering cell signaling and cytokine production will be needed.