Glucocorticoid-induced tumor necrosis factor receptor–related protein co-stimulation facilitates tumor regression by inducing IL-9–producing helper T cells

Kim, Il-Kyu,Kim, Byung-Seok,Koh, Choong-Hyun,Seok, Jae-Won,Park, Jun-Seok,Shin, Kwang-Soo,Bae, Eun-Ah,Lee, Ga-Eun,Jeon, Hyewon,Cho, Jaebeom,Jung, Yujin,Han, Daehee,Kwon, Byoung S,Lee, Ho-Young,Chung, Nature Publishing Group, a division of Macmillan P 2015 Nature medicine Vol.21 No.9

<P>T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) elicits antitumor activity in various tumor models; however, the underlying mechanism of action remains unclear. Here we demonstrate a crucial role for interleukin (IL)-9 in antitumor immunity generated by the GITR agonistic antibody DTA-1. IL-4 receptor knockout (Il4ra(-/-)) mice, which have reduced expression of IL-9, were resistant to tumor growth inhibition by DTA-1. Notably, neutralization of IL-9 considerably impaired tumor rejection induced by DTA-1. In particular, DTA-1-induced IL-9 promoted tumor-specific cytotoxic T lymphocyte (CTL) responses by enhancing the function of dendritic cells in vivo. Furthermore, GITR signaling enhanced the differentiation of IL-9-producing CD4(+) T-helper (T(H)9) cells in a TNFR-associated factor 6 (TRAF6)- and NF-kappa B-dependent manner and inhibited the generation of induced regulatory T cells in vitro. Our findings demonstrate that GITR co-stimulation mediates antitumor immunity by promoting T(H)9 cell differentiation and enhancing CTL responses and thus provide a mechanism of action for GITR agonist-mediated cancer immunotherapies.</P>

OMC-2010 구성약재 배합추출물 투여가 Ovalbumin으로 유도한 마우스 알레르기성 기관지 천식에 미치는 영향

조일주 ( Il Joo Jo ),배기상 ( Gi Sang Bae ),최선복 ( Sun Bok Choi ),송호준 ( Ho Joon Song ),박성주 ( Sung Joo Park ),서상완 ( Sang Wan Seo ),옥주안 ( Joo An Ok ),김민선 ( Min Sun Kim ),백선종 ( Sun Jong Baek ),배익현 ( Ik Hyun Bae 대한본초학회 2013 大韓本草學會誌 Vol.28 No.5

Objectives: We recently have reported that constituents of OMC-2010 have an immuno-modulatory effects via inhibiting tumor necrosis factor (TNF)-alpha and interleukin (IL)-5. In this study, based on previous data, we investigated the effects of combinations with each OMC constituents on splenocyte cytotoxicity, cytokine productions, and ovalbumin (OVA) induced experimental allergic asthma. Methods: Mouse splenocytes were pre-treated with ethanol extract of constituents of Rehmannia glutinosa (RG), Pinellia ternata (PT), Schisandra chinensis (SC). We made 4 combinations using RG, PT, and SC (A;1:1:1, B;2:1:1, C;1:2:1, D;1:1:2). The cells were pretreated with A, B, C, or D for 1 h, then stimulated with lipopolysaccharide (LPS, 1 ㎍/ml) for 48 h. Then the cells were harvested for real-time reverse transcription polymerase chain reaction to detect cytokine productions. Then using effective combination from RG, PR and SC, we administrated the combination orally, then challenged with OVA to induce asthma. Then we analyzed the airway hyper-reactivity (AHR), lung histology and lung TNF-α and IL-5 mRNA. Results: A. B. C. and D did not showed significant cytotoxicity on splenocytes. Pre-treatment of A inhibited the expression of TNF-α and IL-5 significantly, but not B, C, and D. In experimental asthma, administration of A significantly inhibited the increase of AHR, lung damage, TNF-α and IL-5 expression. Conclusions: Theses results could suggest that inhibitory effects of the ideal combination with RG, PT and SC (1:1:1) could be applied to treatment of asthma and study of asthma mechanisms.

The Lipopolysaccharide from Porphyromonas gingivalis Induces Vascular Permeability

Su-Ryun Kim,Seong-Kyoon Jeong,Woo-Sik Kim,Hwa-Jin Jeon,Hyun-Joo Park,Mi-Kyoung Kim,Hye-Ock Jang,Il Yun,Soo-Kyung Bae,Moon-Kyoung Bae KOREAN ACADAMY OF ORAL BIOLOGY 2011 International Journal of Oral Biology Vol.36 No.1

Porphyromonas gingivalis, one of the major periodontal pathogens, is implicated in the initiation and progression of periodontal disease. The initial stages of periodontal inflammation are accompanied by vascular hyperpermeability. In our present study, we report that the P. gingivalis lipopolysaccharide (LPS) increases the mRNA expression of interleukin-8 (IL-8), a major inducer of vascular permeability, in vascular endothelial cells. P. gingivalis LPS also stimulated the induction of IL-8 secretion in endothelial cells. The P. gingivalis LPS-induced expression of IL-8 was primarily modulated by nuclear factor-κB (NF-κB). P. gingivalis LPS significantly enhanced the vascular permeability both in vitro and in vivo, and a blockade of the IL-8 receptor decreased the P. gingivalis LPS-induced vascular permeability. Taken together, these results suggest that P. gingivalis LPS increases vascular permeability through the NF-κBdependent production of IL-8 in vascular endothelial cells.

Activation of NKT Cells in an Anti-PD-1–Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells

Bae, Eun-Ah,Seo, Hyungseok,Kim, Byung-Seok,Choi, Jeongwon,Jeon, Insu,Shin, Kwang-Soo,Koh, Choong-Hyun,Song, Boyeong,Kim, Il-Kyu,Min, Byung Soh,Han, Yoon Dae,Shin, Sang Joon,Kang, Chang-Yuil American Association for Cancer Research 2018 Cancer Research Vol.78 No.18

<P>These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer.</P><P>PD-1–based cancer immunotherapy is a successful example of immune checkpoint blockade that provides long-term durable therapeutic effects in patients with cancer across a wide spectrum of cancer types. Accumulating evidence suggests that anti-PD-1 therapy enhances antitumor immunity by reversing the function of exhausted T cells in the tumor environment. However, the responsiveness rate of patients with cancer to anti-PD-1 therapy remains low, providing an urgent need for optimization and improvement. In this study, we designed an anti-PD-1–resistant mouse tumor model and showed that unresponsiveness to anti-PD-1 is associated with a gradual increase in CD8 T-cell exhaustion. We also found that invariant natural killer T cell stimulation by the synthetic ligand α-galactosylceramide (αGC) can enhance the antitumor effect in anti-PD-1–resistant tumors by restoring the effector function of tumor antigen–specific exhausted CD8 T cells. IL2 and IL12 were among the cytokines produced by αGC stimulation critical for reinvigorating exhausted CD8 T cells in tumor-bearing mice and patients with cancer. Furthermore, we observed a synergistic increase in the antitumor effect between αGC-loaded antigen-presenting cells and PD-1 blockade in a therapeutic murine tumor model. Our study suggests NKT cell stimulation as a promising therapeutic strategy for the treatment of patients with anti-PD-1–resistant cancer.</P><P><B>Significance:</B> These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer. <I>Cancer Res; 78(18); 5315–26. ©2018 AACR</I>.</P>

GM-CSF Promotes Antitumor Immunity by Inducing Th9 Cell Responses

Kim, Il-Kyu,Koh, Choong-Hyun,Jeon, Insu,Shin, Kwang-Soo,Kang, Tae-Seung,Bae, Eun-Ah,Seo, Hyungseok,Ko, Hyun-Ja,Kim, Byung-Seok,Chung, Yeonseok,Kang, Chang-Yuil American Association for Cancer Research 2019 Cancer immunology research Vol.7 No.3

<P>Granulocyte-macrophage colony-stimulating factor (GM-CSF) functions as an adjuvant for antitumor immunity through an unclear mechanism. By activating monocyte-derived dendritic cells, GM-CSF induces Th9 development and IL9 production, which facilitates antitumor cytotoxic T lymphocyte responses.</P><P>GM-CSF as an adjuvant has been shown to promote antitumor immunity in mice and humans; however, the underlying mechanism of GM-CSF–induced antitumor immunity remains incompletely understood. In this study, we demonstrate that GM-CSF potentiates the efficacy of cancer vaccines through IL9-producing Th (Th9) cells. GM-CSF selectively enhanced Th9 cell differentiation by regulating the COX2–PGE<SUB>2</SUB> pathway while inhibiting the differentiation of induced regulatory T (iTreg) cells <I>in vitro</I> and <I>in vivo</I>. GM-CSF–activated monocyte-derived dendritic cells converted tumor-specific nai¨ve Th cells into Th9 cells, and delayed tumor growth by inducing antitumor CTLs in an IL9-dependent manner. Our findings reveal a mechanism for the adjuvanticity of GM-CSF and provide a rationale for the use of GM-CSF in cancer vaccines.</P>

세치제 평가에 있어서 변형실험치은염모형의 안전성

황수정 ( Soo Jeong Hwang ),백대일 ( Dai Il Paik ),김현덕 ( Hyun Duck Kim ),진보형 ( Bo Hyoung Jin ),배광학 ( Kwang Hak Bae ),김남희 ( Nam Hee Kim ) 대한예방치과·구강보건학회 2010 大韓口腔保健學會誌 Vol.34 No.2

연구목적. 일부 연구자들은 치은염 예방 또는 치료 성분이 포함되어 있는 특수세치제의 치은염 억제 효과를 입증하기 위하여 Loe의 실험치은염모형을 변형한 변형실험치은염 모형을 사용하고 있으나, 변형실험치은염모형에 대한 안전성 검토는 미비한 상태이다. 따라서, 본 연구는 3주간 구강분할동시현상비교연구법(split mouth method)을 사용하여 변형실험치은염모형의 안전성을 검토하고 치은염의 일부 기구를 알아보고자 하였다. 연구방법. 성인남자 59명을 대상으로 3주 동안 잇솔질시 잇솔질방지판과 세치제를 편측 소구치부위에 착용하여 기계적 잇솔질을 금지한 실험치은염을 발생시켜 잇솔질방지하악소구치부와 잇솔질허용하악소구치부의 치은염지수, 치면세균막지수, 치은열 구액내의 MMP-9의 농도, IL-1β의 농도를 비교 검토하였다. 연구결과. 잇솔질방지하악소구치부는 3주간의 실험기간동안 실험시작 후 2주차 때 치은염지수와 치면세균막지수가 가장 높았으며 시간에 따라 차이변화가 유의하였으며(p<0.02) 실험 종료 후 초기상태로 회복되었다. 3주간의 실험기간동안 잇솔질방지하악 소구치부와 잇솔질허용하악소구치부 사이에서는 치은열구액내 염증지표인 MMP-9의 농도변화는 유의하지 않았고 염증전단계지표인 IL-1β의 농도변화는 유의하였으나(p=0.03) 잇솔질방지하악소구치부의 MMP-9의 농도와 IL-1β의 농도는 유의한 상관 관계를 보였다. 결론. 잇솔질방지하악소구치부내 MMP-9의 농도는 유의하게 변화하지 않았으므로 치은의 직접적인 파괴는 나타나지 않은 것으로 사료되어 변형실험치은염모형은 세치제의 효과를 평가함에 있어 안전한 모형으로 사료되었다.

LPS로 유도한 RAW 264.7 세포의 염증반응에서 자초(紫草)의 항염증 효과

최선복 ( Sun Bok Choi ),배기상 ( Gi Sang Bae ),조일주 ( Il Joo Jo ),박경철 ( Kyoung Chel Park ),서승희 ( Seung Hee Seo ),김동구 ( Dong Goo Kim ),신준연 ( Joon Yeon Shin ),곽태신 ( Tae Sin Gwak ),이정현 ( Jung Hyun Lee ),이금산 ( G 대한본초학회 2013 大韓本草學會誌 Vol.28 No.2

Objective: Lithospermum Erythrorhizon (LE) has been used as an anti-bacterial and anti-inflammatory agent. However, it is unclear that LE aqueous extract could show the anti-inflammatory effects in RAW 264.7cells. The purpose of this study was to investigate the anti-inflammatory effect of aqueous extract from LE on lipopolysaccharide (LPS) - induced inflammatory response. Methods: To measure out the cytotoxicity of LE, we performed the MTT assay. To evaluate the anti-inflammatory effects of LE, we examined the inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2) and pro-inflammatory cytokines (tumor necrosis factor (TNF)-a, interleukin, (IL)-1β and (IL)-6) on RAW 264.7 cells. We also examined molecular mechanisms such as mitogen-activated protein kinases (MAPKs) and nuclear factor-B (NF-κB) activation by western blot. Results : Aqueous Extract from LE itself did not have any cytotoxic effect in RAW 264.7 cells. Aqueous extract from LE inhibited LPS-induced productions of inflammatory mediators such as NO, PGE2, and pro-inflammatory cytokines including TNF-a, IL-1β and IL-6 in RAW 264.7cells. In addition, LE inhibited the phosphorylation of p38 kinases (p38), c-Jun NH2-terminal kinase (JNK), and NF-κB activation in RAW 264.7 cells. Conclusion : LE down-regulated LPS-induced production of inflammatory mediators through the inhibition of p38, JNK and NF-κB activation. Taken together, these results could provide the evidence for the anti-inflammatory effects of LE. Therefore, LE may be a novel target in the management of inflammation and help to support a potential strategy for prevention and therapy of inflammatory diseases.

Therapeutic effect of a novel histone deacetylase 6 inhibitor, CKD-L, on collagen-induced arthritis in vivo and regulatory T cells in rheumatoid arthritis in vitro

Oh, Bo Ram,Suh, Dong-hyeon,Bae, Daekwon,Ha, Nina,Choi, Young Il,Yoo, Hyun Jung,Park, Jin Kyun,Lee, Eun Young,Lee, Eun Bong,Song, Yeong Wook BioMed Central 2017 Arthritis research & therapy Vol.19 No.-

<P><B>Background</B></P><P>Histone deacetylase (HDAC) inhibitor has recently been reported to have a therapeutic effect as an anti-inflammatory agent in collagen-induced arthritis (CIA). We investigated the therapeutic effect of a new selective HDAC6 inhibitor, CKD-L, compared to ITF 2357 or Tubastatin A on CIA and regulatory T (Treg) cells in patients with rheumatoid arthritis (RA).</P><P><B>Methods</B></P><P>CIA was induced by bovine type II collagen (CII) in DBA/1 J mice. Mice were treated with HDAC inhibitor for 18 days. Arthritis score was assessed and histological analysis was performed by hematoxylin and eosin (H&E) stain. Cytotoxic T-lymphocyte associated protein (CTLA)-4 expression in induced Treg cells was analyzed and suppression assay was analyzed using Treg cells and effector T (Teff) cells isolated from naive C57BL/6 mice by flow cytometry. Cytokines were analyzed in peripheral blood mononuclear cells (PBMC) of five patients with RA by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR). Tumor necrosis factor (TNF) was analyzed using PMA- activated THP-1 cells by ELISA. Suppression assay was analyzed using Treg cells and Teff cells isolated from RA patients by flow cytometry.</P><P><B>Results</B></P><P>In the CIA model, CKD-L and Tubastatin A significantly decreased the arthritis score. CKD-L increased CTLA-4 expression in Foxp3<SUP>+</SUP> T cells and inhibited the proliferation of Teff cells in the suppression assay. In RA PBMC, CKD-L significantly inhibited TNF and interleukin (IL)-1β, and increased IL-10. CKD-L and Tubastatin A inhibited TNF secretion from PMA-activated THP-1 cells. CKD-L and ITF 2357 inhibited the proliferation of Teff cells in RA patients in the suppression assay. Tubastatin A had no effect on inhibition of proliferation.</P><P><B>Conclusion</B></P><P>CKD-L decreased the arthritis score in CIA, reduced the expression of TNF and IL-1β, and increased the expression of IL-10 in PBMC from RA patients. CKD-L increased CTLA-4 expression and the suppressive function of Treg cells. These results suggest that CKD-L may have a beneficial effect in the treatment of RA.</P>

Effects of Moxibustion to Zusanli(ST36) on Alteration of Natural Killer Cell Activity in Rats

Choi, Gi Soon,Han, Jae Bok,Park, Joon Ha,Oh, Sang Deog,Lee, Gi Seog,Bae, Hyun Su,Jung, Sung Ki,Cho, Young Wuk,Ahn, Hyun Jong,Min, Byung Il WHO COLLABORATING CENTRE FOR TRADITIONAL MEDICINE 2004 東西醫學硏究所 論文集 Vol.2004 No.-

Moxibustion is one of the major healing techniques in Oriental medicine. It has been widely used in many diseases such as rheumatoid arthritis, Hashimoto disease, breech presentation, etc. However, till now, effects of moxibustion on natural killer (NK) cell activity and relations between sympathetic nerve system (SNS) and the immune alteration induced by moxibustion wert not well studied. This study was designed to evaluate effects of moxibustion on NK cell activity and the Intervention of SNS in the alteration of NK cell activity induced by moxibustion. Splenic NK cell cytotoxicity was measured in a standard 4-hour ^(51)Cr release assay. We measured the NK cell cytotoxicity after moxibustion stimulation for 1, 3, 5 and 7 days, and also measured the NK cell cytotoxicity after 3 and 7 days burn stimulation with similar temperature. Interleukin (IL)-2, -4 and interferon (INF)-γ in serum were measured by rat IL-2, -4 and INF-γ ELISA test kit. To evaluate the effects of sympathectomy on alteration of NK cell cytotoxicity, 6-hydroxydopamine (6-OHDA: 50 mg/kg) was used. We showed that NK cell activity of moxibustion stimulation group incrcased at the 3rd day, and declined at the 7th day in comparison with that of the control group. In thc moxibustion stimulation group, NK cell activity was significantly higher than the sham group at the 3rd day. On the contrary, in the burn stimulation group, NK cell activity was significantly higher than that of the sham groups at 3rd and 7th days. INF-γ level after 3 days in the moxibustion stimulation group was significantly higher than that of the sham group. IL-2 Ievel among groups were not different. IL-4 was not detected in serum with this method. Sympathectomy abolished the NK cell activity alteration induced by moxibustion. The results suggest that moxibustion modulates NK cell activity, along with INF-γ, and SNS is mediating these effects.

캠퍼스 외부공간의 개선방안에 관한 연구 : 목포대학교 도림캠퍼스를 대상으로

배현미,최일 木浦大學校 工業技術硏究所 2000 工業技術硏究誌 Vol.10 No.-

For the purpose of reconsidering the spatial structure in University campus, this study was carried out. Namely, in this study, we investigated whether the open-space in campus was to be compatible for the purpose and a designer's intention by the analysis and to examine the present conditions. As the result of these estimation, it was to propose the improvement method of open-space in campus. Research content and results were as follows. It was carried out the analysis of the land utilization and space arrangement at first stage and to examine the problems and present conditions in open-space at second stage. Based on the alteration planning, at 3rd stage, we propose the open-space planning on the assumption that an expansion planning will be advance. Finally, we also propose the proposal of open-space in Torim campus which has to reconsidering for the necessity of overall modification and partial supplementation.