• Development and Reproduction
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• v.24 no.1
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• pp.53-62
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• 2020

Natural killer (NK) cells are innate lymphocytes that play an essential role in preventing cancer development by performing immune surveillance to eradicate abnormal cells. Since ex vivo expanded NK cells have cytotoxic activity against various cancers, including breast cancers, their clinical potential as immune-oncogenic therapeutics has been widely investigated. Here, we report that the pyrazole chemical XRP44X, an inhibitor of Ras/ERK activation of ELK3, stimulates NK-92MI cells to enhance cytotoxic activity against breast cancer cells. Under XRP44X stimulation, NK cells did not show notable apoptosis or impaired cell cycle progression. We demonstrated that XRP44X enhanced interferon gamma expression in NK-92MI cells. We also elucidated that potentiation of the cytotoxic activity of NK-92MI cells by XRP44X is induced by activation of the c-JUN N-terminal kinase (JNK) signaling pathway. Our data provide insight into the evaluation of XRP44X as an immune stimulant and that XRP44X is a potential candidate compound for the therapeutic development of NK cells.

• Biomedical Science Letters
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• v.20 no.2
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• pp.96-102
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• 2014

Staphylococcal enterotoxin B (SEB) is bacterial toxin that induces the activation of immune cells. Because the inhibition of pro-inflammatory effect of SEB can resolve the inflammation, I determined the influence of functional or structural change of SEB on immune cells. The post translational modification of protein occurs through carbamylation. Carbamylation can change the structure of proteins and can modify the biological activity of protein. In the present study, I investigated the effect of carbamylated SEB (CSEB) on the inflammatory response mediated by LPS in HL-60 cells. To determine the anti-inflammatory effect of CSEB, I produced carbamylated SEB using potassium cyanate (KCN) and then examined whether CSEB involved in cytokine releases and apoptosis of LPS-stimulated HL-60 cells. Although CSEB had not any effect on the LPS-stimulated HL-60 cells, the protein levels of IL-8, TNF-${\alpha}$ and IL-$1{\beta}$ were significantly decreased by CSEB without cytotoxicity. CSEB also blocked Akt and NF-${\kappa}B$ activation. These results indicate that the suppressive effect of CSEB in LPS-stimulated cytokine releases is occurred by inhibition of Akt and NF-${\kappa}B$ activity. Through further studies, CSEB may be used as anti-inflammatory molecule that makes the immune system more efficient.

• BMB Reports
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• v.39 no.6
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• pp.788-793
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• 2006

Bacterial DNA containing immunostimulatory CpG motifs can stimulate antigen-presenting cells to express co-stimulatory molecules and to produce various cytokines in vivo and in vitro. In this study, we fragmented macromolecular E.coli genomic DNA with DNase I, and analyzed the ability of the resulting DNA fragments to induce the NF-${\kappa}B$ activation and humoral immune response. Furthermore, using computational analysis and luciferase assay for synthetic ODNs based on the sequence of the immunostimulatory DNA fragments (DF-ODNs), an active component of DF-ODNs sequences was investigated. Experimental results demonstrated that DF-ODN is optimal for the NF-${\kappa}B$-responsive promoter activation in the mouse macrophage cell line and the humoral immune response in vivo. In agreement with the activity of the DF-ODNs processed by DNase I, a synthetic ODN based on the DF-ODN sequences is potent at inducing IL-12 mRNA expression in primary dendritic cells. These results suggest that the discovery and characterization of a highly active natural CpG-ODN may be achieved by the analyses of bacterial DNA fragments generated by a nuclease activity.

• Korean Journal of Veterinary Research
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• v.53 no.3
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• pp.143-147
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• 2013

Ginsenoside Rp1 is one of ginseng saponins with chemotherapeutic activity. In this study, we investigated the effects of Rp1 on spleen cells. Spleen is a major immune organ consisted of crucial immune cells, such as T lymphocytes, B lymphocytes, natural killer cells, and some antigen-presenting cells. Although the anti-tumor potential of Rp1 was studied, the effects of Rp1 on immune cells have not investigated yet. A viability assay using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT), flow cytometric analysis, Western blot analysis were used to detect cellular changes on Rp1-treated spleen cells. MTT assay showed that Rp1 decreased the viability of spleen cells. To further investigate the effects of Rp1 on activated spleen cells, we treated lipopolysaccharide (LPS) as a representative inflammatory agent and Rp1 on spleen cells in a combination. The surface expression levels of activation markers for lymphocytes, CD25 and CD69 were measured. Apoptotic analysis revealed the cytotoxic effects of Rp1 on both na$\ddot{i}$ve and activated cells, and the expression pattern of some apoptosis-related proteins was correlated to apoptotic events of cells. Taken together, ginsenoside Rp1 increases the cellular death of spleen cells and also inhibits the LPS-induced activation of spleen cells.

• Journal of Microbiology and Biotechnology
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• v.29 no.8
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• pp.1248-1254
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• 2019

Identification of novel probiotic strains is of great interest in the field of functional foods. Specific strains of heat-killed bacteria have been reported to exert immunomodulatory effects. Herein, we investigated the immune-stimulatory function of heat-killed Lactobacillus plantarum KCTC 13314BP (LBP). Treatment with LBP significantly increased the production of $TNF-{\alpha}$ and IL-6 by macrophages. More importantly, LBP was able to enhance the phagocytic activity of macrophages against bacterial particles. Activation of p38, JNK, ERK, $NF-{\kappa}B$, and STAT3 was involved in the immunomodulatory function of LBP. LBP treatment significantly increased production of $TNF-{\alpha}$ by bone marrow-derived macrophages and splenocytes, further confirming the immunostimulatory effect of LBP in primary immune cells. Interestingly, the immunomodulatory effects of LBP were much stronger than those of Lactobacillus rhamnosus GG, a well-known probiotic strain. These results indicate that LBP can be a promising immune-enhancing functional food agent.

• Korean Journal of Plant Resources
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• v.36 no.3
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• pp.191-197
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• 2023

Autophagy contributes to enhancing the immune system (innate and adaptive immune system) against foreign pathogens. Autophagy of macrophages is used as a major indicator for developing vaccine adjuvants to increase the adaptive immune response. In this study, HSL increased p62/SQSTM1 expression. Inhibition of TLR4, p38, JNK, and NF-κB blocked HSL-mediated increase of p62/SQSTM1. HSL activated p38, JNK, and NF-κB signaling, but HSL-mediated activation of p38, JNK, and NF-κB signaling was reversed by TLR4 inhibition. In addition, HSL increased Nrf2 expression, but HSL-mediated Nrf2 expression did not occur in the inhibition of TLR4, p38, JNK, and NF-κB. Taken together, it is believed that HSL-mediated autophagy may be dependent on activating Nrf2 expression via TLR4-dependent activation of p38, JNK, and NF-κB in macrophages.

• IMMUNE NETWORK
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• v.19 no.1
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• pp.2.1-2.13
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• 2019

The enhanced differentiation and activation of osteoclasts (OCs) in the inflammatory arthritis such as rheumatoid arthritis (RA) and gout causes not only local bone erosion, but also systemic osteoporosis, leading to functional disabilities and morbidity. The induction and amplification of NFATc1, a master regulator of OC differentiation, is mainly regulated by receptor activator of NF-κB (RANK) ligand-RANK and calcium signaling which are amplified in the inflammatory milieu, as well as by inflammatory cytokines such as TNFα, IL-1β and IL-6. Moreover, the predominance of CD4⁺ T cell subsets, which varies depending on the condition of inflammatory diseases, can determine the fate of OC differentiation. Anti-citrullinated peptide antibodies which are critical in the pathogenesis of RA can bind to the citrullinated vimentin on the surface of OC precursors, and in turn promote OC differentiation and function via IL-8. In addition to adaptive immunity, the activation of innate immune system including the nucleotide oligomerization domain leucine rich repeat with a pyrin domain 3 inflammasome and TLRs can regulate OC maturation. The emerging perspectives about the diverse and close interactions between the immune cells and OCs in inflammatory milieu can have a significant impact on the future direction of drug development.

• The Journal of Korean Obstetrics and Gynecology
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• v.27 no.2
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• pp.46-58
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• 2014

Objectives: This study was designed to investigate intestinal immune system activation and anti-metastatic effect on cancer cells by orally administered extracts of Boyanghwano-tang. Methods: To observe immunomodulating effects of Boyanghwano-tang on Peyer's patch cells, we measured cytokines GM-CSF, IL-4. In addition to observing effects of Boyanghwano-tang on hematopoiesis, we measured proliferation of bone marrow cells mediated by Peyer's patch cells in vitro. IgA induction activated in intestinal content and serum was measured to observe the effect of orally administered Boyanghwano-tang on mucosal immune system. After administering ovalbumin (OVA) with Boyanghwano-tang, Proliferation of Peyer's patch cell was measured to investigate gut immunostimulatory effect. Anti-metastatic experiments were conducted in vivo mouse model by using colon 26-M3.1 carcinoma cell. Results: The amounts of GM-CSF and IL-4 in the culture supernatant of Peyer's patch cells were significantly increased compared to the control group. The proliferation of bone marrow cell was significantly up-regualted with Boyanghwano-tang. These results indicate that oral administration of Boyanghwano-tang enhances the secretion of hematopoietic growth factors such as GM-CSF and IL-4 from Peyer's patch cells, and these cytokines also act on modulator of bone marrow cell proliferation. After orally administering OVA with Boyanghwano-tang, IgA induction and Proliferation of peyer's patch cell was up-regulated with Boyanghwano-tang. These results means orally administered Boyanghwano-tang activates intestinal immune system and has an inhibitory effect on tumor metastasis. In addition, We found that orally administered Boyanghwano-tang significantly inhibited tumor metastasis in vivo. Conclusions: Orally administered Boyanghwano-tang appears to have considerable activity on the anti-metastasis by activation of immune system.

• The Journal of Korean Obstetrics and Gynecology
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• v.27 no.2
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• pp.34-45
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• 2014

Objectives: This study was designed to investigate intestinal immune system activation and antimetastatic effect of Ojeok-san on cancer cells by oral administration. Methods: Cell viability of Ojeok-san was tested with colon 26-M3.1 carcinoma cells and Peyer's patch cells in vitro. Antimetastatic experiments were conducted in vivo mouse model by using colon 26-M3.1 carcinoma cell. To observe immunomodulating effects of Ojeok-san on Peyer's patch cells, we measured interleukin (IL)-4, GM-CSF. In addition to observing effects of Ojeok-san on hematopoiesis, we measured proliferation of bone marrow cells mediated by Peyer's patch cells in vitro. IgA induction activated in serum and intestinal content was measured to observe the effect of orally administered Ojeok-san on mucosal immune system. After administering Ovalbumin (OVA) with Ojeok-san, Proliferation of Peyer's patch cell was measured to investigate gut immunostimulatory effect. Results: in vitro cytotoxicity analysis, the inhibitory concentration $(IC)_{50}$ of the colon 26-M3.1 carcinoma cell was $890{\mu}g/ml$. $IC_{50}$ of the Peyer's patch cells with LPS was $990{\mu}g/ml$. We found that orally administered Ojeok-san significantly inhibited tumor metastasis in vivo. In addition, the amounts of IL-4 and GM-CSF in the culture supernatant of Peyer's patch cells were significantly increased compared to the control group. The proliferation of bone marrow cell was significantly up-regulated with Ojeok-san. These results indicate that oral administration of Ojeok-san enhances the secretion of hematopoietic growth factors such as GM-CSF and IL-4 from Peyer's patch cells, and these cytokines also act on modulator of bone marrow cell proliferation. After orally administering Ovalbumin (OVA) with Ojeok-san, IgA induction and Proliferation of peyer's patch cell was up-regulated with Ojeok-san. These results means orally administered Ojeok-san activates intestinal immune system and has an inhibitory effect on tumor metastasis. Conclusions: Orally administered Ojeok-san appears to have considerable activity on the anti-metastasis by activation of immune system.

• International Journal of Oral Biology
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• v.42 no.3
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• pp.85-90
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• 2017

Mitochondria participate in various intracellular metabolic pathways such as generating intracellular ATP, synthesizing several essential molecules, regulating calcium homeostasis, and producing the cell's reactive oxygen species (ROS). Emerging studies have demonstrated newly discovered roles of mitochondria, which participate in the regulation of innate immune responses by modulating NLRP3 inflammasomes. Here, we review the recently proposed pathways to be involved in mitochondria-mediated regulation of inflammasome activation and inflammation: 1) mitochondrial ROS, 2) calcium mobilization, 3) nicotinamide adenine dinucleotide ($NAD^+$) reduction, 4) cardiolipin, 5) mitofusin, 6) mitochondrial DNA, 7) mitochondrial antiviral signaling protein. Furthermore, we highlight the significance of mitophagy as a negative regulator of mitochondrial damage and NLRP3 inflammasome activation, as potentially helpful therapeutic approaches which could potentially address uncontrolled inflammation.