A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor β Subunit, Glycoprotein 130

Hong, Soon-Sun,Choi, Jung Ho,Lee, Sung Yoon,Park, Yeon-Hwa,Park, Kyung-Yeon,Lee, Joo Young,Kim, Juyoung,Gajulapati, Veeraswamy,Goo, Ja-Il,Singh, Sarbjit,Lee, Kyeong,Kim, Young-Kook,Im, So Hee,Ahn, Sun The American Association of Immunologists, Inc. 2015 JOURNAL OF IMMUNOLOGY Vol.195 No.1

<P>IL-6 is a major causative factor of inflammatory disease. Although IL-6 and its signaling pathways are promising targets, orally available small-molecule drugs specific for IL-6 have not been developed. To discover IL-6 antagonists, we screened our in-house chemical library and identified-LMT-28, a novel synthetic compound, as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular target of LMT-28 were investigated. A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, LMT-28 downregulated IL-6-stimulated phosphorylation of STAT3, gp130, and JAK2 protein and substantially inhibited IL-6-dependent TF-1 cell proliferation. LMT-28 antagonized IL-6-induced TNF-alpha production in vivo. In pathologic models, oral administration of LMT-28 alleviated collagen-induced arthritis and acute pancreatitis in mice. Based on the observation of upstream IL-6 signal inhibition by LMT-28, we hypothesized IL-6, IL-6R alpha, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6R alpha complex binding to gp130 in the presence of LMT-28, which was measured by surface plasmon resonance analysis. Taken together, our data suggest that LMT-28 is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130.</P>

이질아메바에 의한 인체 대장상피세포주 HT-29에서의 interleukin-8 유전자의 발현

김정목,정현채,임경일,조양자,김정룡 INSTITUTE OF TROPICAL MEDICINE YONSEI UNIVERSITY 1995 YONSEI REPORTS ON TROPICAL MEDICINE Vol.26 No.1

이질아메바에 의한 장염 환자의 조직 또는 이질아메바를 실험적으로 감염시킨 동물의 조직 검사에서 호중구의 침윤이 특징적으로 관찰된다. 그러나 이와같은 호중구의 침윤을 설명할 수 있는 기전에 대한 연구는 매우 미흡하다. 따라서 본 연구자들은 아메바 감염 초기에 인체 대장상피세포에서 interleukin-8(IL-8)이 유도되어 호중구 침윤과 같은 염증반응이 유발될 것이라는 가설을 설정하였다. 이를 위하여 인체 대장상피세포주인 HT-29에 이질아메바 영양형을 실험적으로 노출시킨 뒤 발현되는 IL-8 mRNA를 역전사 중합효소법(reverse transcriptional polymerase chain reaction, RT-PCR)으로 검사함과 동시에 발현된 IL-8 mRNA를 인공적으로 합성시킨 표준 RNA와 RT-PCR법을 이용하여 정량하였다. 실험 결과 이질아메바 영양형에 노출된 30분 후 부터 IL-8 mRNA가 발현되기 시작하였다. 그리고 그 발현 분자수는 노출 시간의 증가에 따라 계속 증가하여 3시간 대에는 3.1×10(7) molecules/㎍ total RNA를 나타내었다. 동시에 IL-8 mRNA의 발현은 노출시킨 이질아메바 영양형의 수에 비례하였다. 즉, HT-29/아메바 영양형의 비율이 10:1인 경우 IL-8 mRNA의 발현 분자수는 1.2×10(7) molecules/㎍ total RNA로 나타났다. 이와같은 IL-8 mRNA의 발현은 IL-8 단백질 분비로 이어짐을 ELISA 검사로 확인할 수 있었다. 한편 이질아메바 파쇄액(lysate)도 대장상피세포주인 Caco-2에서 IL-8 mRNA발현을 유도하였다. 결론적으로 본 실험은 이질아메바 감염 초기에 대장상피세포로 부터 IL-8이 발현되며 이에 의하여 염증반응이 촉발될 가능성이 있음을 시사해 준다. The protozoan parasite, Entamoeba histolytica, is one of major causative agents of intestinal disease all over the world. In acute experimental infection, the early host response to E. histolytica is characterized by an infiltration of neutrophils. However, the chemotactic signal for this response is not well known. Based on the finding that human epithelial cells produce the potent neutrophil chemoattractant and activator, interlukin-8 (IL-8), IL-8 gene expression was examined thoroughly in human colon epithelial cells exposed to E. histolytica trophozoites. Cellular RNAs were extracted from HT-29 or Caco-2 human colon epithelial cells exposed to E. histolytica trophozoities for 30 minutes. 1 and 3 hours. IL-8 mRNA transcripts were measured by reverse transcriptional polymerase chain reaction (RT-PCR) using synthetic standard RNA. The number of IL-8 mRNA molecules increased from 30 minutes to 3 hours of exposure period, reaching 3.1×10(7) molecules/㎍ of total RNA. Expression pattern of IL-8 mRNA transcripts was parallel to the amounts of IL-8 protein measured by enzyme-linked immunosorbent assay (ELISA). Lysates of E. histolytica also induced expression of mRNA for IL-8 in colon epithelial cells. These results suggest that acute inflammatory reaction by E. hisstolytica may be initially triggered by proinflammatory cytokines such as IL-8 secreted from epithelial cells of the colon.

Interleukin-2가 호산구 생존에 미치는 영향과 기전에 관한 연구

김효석 ( Hyo Seok Kim ),이영목 ( Young Mok Lee ),최영수 ( Young Soo Choi ),김경호 ( Kyung Ho Kim ),임건일 ( Geon Il Im ),문승혁 ( Jeong Sung Whan ),정성환 ( Moon Seung Hyug ),김현태 ( Hyeon Tae Kim ),어수택 ( Uh Soo Taek ),김용훈 대한결핵 및 호흡기학회 1996 Tuberculosis and Respiratory Diseases Vol.43 No.3

Poster Session:PS 0239 ; Gastroenterology : Vitamin C Insuffi ciency Aggravates Dextran Sulfate Sodium (DSS)-Induced Colitis in Gulo(-/-) Mice

( Hye Min Kim ),( Jae Seung Kang ),( Jong Pil Im ),( Se Yeon Bae ),( Ye Jin Kim ),( Hang Rae Kim ),( Joo Sung Kim ),( Young Il Hwang ),( Wang Jae Lee ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Background: Mucosal damage in inflammatory bowel diseases (IBDs) involves the dysfunctional immunoregulation of the gut. Among immunoregulatory factors, oxidative stress is abnormally high level in IBDs, and their destructive effects may contribute to the initiation or propagation of the disease. Vitamin C has both anti-oxidant and immunomodulatory effects. Methods: we investigated the effect of vitamin C on dextran sulfate sodium (DSS)-induced colitis in Gulo(-/-) mice which cannot synthesize vitamin C. Results: Vitamin C-insufficient Gulo(-/-) mice showed decreased survival with increased oxidative stress and more severe colitis. The production of interleukin (IL)-6 was higher, and STAT3 and Akt were more activated in DSS-treated vitamin C-insuffi cient Gulo(-/-) mice than in vitamin C-suffi cient Gulo(-/-) mice and wild-type mice. In contrast, the production of IL-22, the recruitment of NKp46(+) cells, and the activation of p38 MAPK were decreased in the vitamin C-insuffi cient Gulo(-/-) mice accompanied by decreased mucin-1 expression. Taken together, vitamin C insuffi ciency was associated with not only increased oxidative stress and IL-6 production but also decreased production of IL-22, which eventually induces severe colitis and death by DSS treatment. Conclusions: Therefore, our results suggest that vitamin C has a protective effect on DSS-induced colitis by regulating the production of cytokine and the induction of infl ammation.

활성 RAW 264.7 세포에서 항염증 및 자외선 유도 마우스 피부손상의 개선에 대한 새송이 추출물의 효과

조병옥(Byoung Ok Cho),윤홍화(Hong Hua Yin),이현서(Hyun-Seo Lee),추정임(Jung Im Chu),장선일(Seon Il Jang) 한국식품과학회 2017 한국식품과학회지 Vol.49 No.1

본 연구는 먼저 새송이버섯 추출물인 PEE가 활성화된 면역세포에서 항염증 효과가 있는지 알아보았다. 그 결과 LPS로 자극된 RAW 264.7 세포에 PEE를 처리했을 때 5과 15 mg/mL 등 높은 농도에서 NO를 효과적으로 억제하였다. 그리고 LPS가 유도하는 IL-1β와 IL-6는 5 mg/mL 농도에서는 억제 없었으나, 15 mg/mL 농도에서 현저히 억제하는 효과가 있었다. 다음은 UVB가 유도하는 C57BL/6 마우스 피부손상에 대한 PEE의 개선 효과에 대해서 알아보았다. PEE를 7일간 경구투여한 후 7일, 10, 13일 등 3일 간격으로 하루에 1회씩 UVB (250 mJ/cm²)로 마우스 등 피부에 조사하여 피부손상을 유발하였다. UVB 조사 후부터는 PEE를 경구투여와 함께 피부에 도포하여 PEE가 피부 손상에 대한 개선 효과를 조사하였다. 그 결과 PEE 투여군은 UVB로 유도되는 표피두께, 홍반지수 및 멜라닌 지수가 참고약물로 사용한 비타민 C(AA) 투여군과 유사한 개선되는 효과가 있었다. 또한 PEE투여군은 UVB가 유도하는 비만세포를 비롯한 염중세포 침윤이 현저히 억제되는 효과가 있었다. 이상의 결과를 종합해볼 때 PEE는 항염증 효과와 더불어 UVB가 유도하는 피부손상을 개선하는 우수한 효과가 있어 기능성 식품소재 및 화장품 소재로 활용할 수 있을 것으로 판단된다. The aim of this study was to investigate the anti-inflammatory and ultraviolet (UV)-protective effect of Pleurotus eryngii extract (PEE) in activated RAW 264.7 cells and UV-induced mouse skin damage. The results showed that PEE strongly inhibited the production of inflammatory mediators such as nitric oxide, interleukin (IL)-1β, and IL-6 at high concentrations in LPS-stimulated RAW 264.7 macrophages. In addition, PEE treatment suppressed erythema, melanin index, and epidermal thickness to a greater degree than ascorbic acid (AA) treatment in UV-irradiated mice. Finally, PEE treatment inhibited the infiltration of mast cell to a similar degree of AA treatment. Therefore, these results indicate that PEE could improve inflammation and skin damage in immune cells and UV-irradiated mice. This study may provide positive insights into PEE as a functional food and cosmetic ingredient for treatment of inflammation and skin damage.

포도가지와 새송이버섯 혼합 추출물의 항염증과 아토피 피부염 개선 상승효과

윤홍화(Hong Hua Yin),조병옥(Byoung Ok Cho),이혜승(Hye Seung Lee),추정임(Jung Im Chu),장선일(Seon Il Jang) 한국식품과학회 2016 한국식품과학회지 Vol.48 No.6

본 연구는 캠벨어얼리 포도가지와 새송이버섯 혼합 추출물이 활성화된 면역세포에서 항염증 및 화학항원과 생물학적 항원을 동시에 처리한 아토피 피부염 유사 모델 마우스에서 아토피 개선에 대한 상승효과를 알아보았다. 그 결과 지방질다당류로 자극된 RAW 264.7 세포에 포도가지와 새송이버섯 각각의 추출물 처리했을 때 보다 이들 추출물을 혼합하여 처리할 때 산화질소와 PGE2 생성을 효과적으로 억제하였다. 또한 지방질다당류로 자극된 RAW 264.7 세포와 PMA와 A23187로 활성화된 HMC-1 세포에서도 각각의 추출물 보다 혼합추출물을 처리했을 때 TNF-α와 IL-6 생성에 대한 억제 효과가 매우 우수하였다. 더욱이 DNCB와 집먼지진드기 항원으로 유도된 아토피 피부염 유사 모델에서 포도가지와 새송이버섯 혼합 추출물 투여는 각각의 추출물 투여에 비해서 외부적 피부병변과 피부두께 및 피부조직학적 등 임상적으로 아토피 피부염에 대한 개선 효과가 매우 뛰어남을 확인할 수 있었다. 이러한 포도가지와 새송이버섯 혼합 추출물의 아토피 피부염 개선 효과는 혈청 내 IgE와 IL-4의 생성을 억제함으로써 각각의 추출물에 비해서 상승되는 효과가 있음을 나타내 주었다. 이러한 결과는 포도가지와 새송이버섯 각각의 추출물 투여보다는 이들의 추출물을 혼합하여 투여하는 것이 아토피 피부염을 개선시키는데 효과적임을 알 수 있었다. The aim of this study was to investigate the synergistic anti-inflammatory and anti-dermatitis effects of grape branch extract (GBE) and Pleurotus eryngii (PEE) combinations on the active immune cells and atopic dermatitis-like skin lesions in mice. The results showed that the combination of GBE (12.5 μg/mL) and PEE (500 μg/mL) led to much stronger inhibitory effects on the production of inflammatory mediators, such as NO and PGE2 than that exhibited by GBE(25 μg/mL) and PEE (1000 μg/mL) alone, even at higher concentrations, in LPS-stimulated RAW 264.7 macrophages. The combination of GBE and PEE synergistically inhibited the production of TNF- and IL-6 in LPS-stimulated RAW 264.7 macrophages and PMA plus A23187-activated HMC-1 cells. Furthermore, combined GBE and PEE had a stronger ameliorative effect than GBE and PEE alone by inhibiting the clinical sores, IgE, and IL-4 on atopic dermatitis-like skin lesions in mice. Collectively, these results suggested that the combination of GBE and PEE produced a synergistic antiinflammatory and anti-atopic dermatitis effect on immune cells and atopic dermatitis-like skin lesions in mice.

IL-21-Expressing Mesenchymal Stem Cells Prevent Lethal B-Cell Lymphoma Through Efficient Delivery of IL-21, Which Redirects the Immune System to Target the Tumor

Kim, Nayoun,Nam, Young-Sun,Im, Keon-Il,Lim, Jung-Yeon,Lee, Eun-Sol,Jeon, Young-Woo,Cho, Seok-Goo Mary Ann Liebert 2015 STEM CELLS AND DEVELOPMENT Vol.24 No.23

The Free Radical Scavenger NecroX-7 Attenuates Acute Graft-versus-Host Disease via Reciprocal Regulation of Th1/Regulatory T Cells and Inhibition of HMGB1 Release

Im, Keon-Il,Kim, Nayoun,Lim, Jung-Yeon,Nam, Young-Sun,Lee, Eun-Sol,Kim, Eun-Jung,Kim, Hyoung Jin,Kim, Soon Ha,Cho, Seok-Goo The American Association of Immunologists, Inc. 2015 JOURNAL OF IMMUNOLOGY Vol.194 No.11

<P>Graft-versus-host disease (GVHD) is a major complication associated with allogeneic hematopoietic stem cell transplantation. Despite the prominent role of the adaptive immune system, the importance of controlling the innate immune system in the pathogenesis of GVHD has recently been rediscovered. High-mobility group box 1 (HMGB1) is a crucial damage-associated molecular pattern signal that functions as a potent innate immune mediator in GVHD. In the present study, we investigated treatment of experimental GVHD through HMGB1 blockade using the compound cyclopentylamino carboxymethylthiazolylindole (NecroX)-7. Treated animals significantly attenuated GVHD-related mortality and inhibited severe tissue damage. These protective effects correlated with the decrease in HMGB1 expression and lower levels of reactive oxidative stress. Additionally, NecroX-7 inhibited the HMGB1-induced release of TNF and IL-6, as well as the expression of TLR-4 and receptor for advanced glycation end products. We also observed increased regulatory T cell numbers, which may be associated with regulation of differentiation signals independent of HMGB1. Taken together, these data indicate that NecroX-7 protects mice against lethal GVHD by reciprocal regulation of regulatory T/Th1 cells, attenuating systemic HMGB1 accumulation and inhibiting HMGB1-mediated inflammatory response. Our results indicate the possibility of a new use for a clinical drug that is effective for the treatment of GVHD.</P>

국내·외 시험불안 연구의 메타분석

임신일(Shin Il Im),박병기(Byung Gee Bak) 한국교육심리학회 2013 敎育心理硏究 Vol.27 No.3

이 연구의 목적은 최근까지 국내·외에서 다뤄온 시험불안과 관련 있는 변인들의 관계와 시험붙안 감소 프로그램들의 효과를 분석하고 종합하는 것이다. 이를 위해 19개국에서 그동안 실시된 시험불 안 연구를 수집하였다. 시험불안과 관련된 변인의 관계를 분석하기 위해 총 348편의 논문에서 3293 개의 상관 효과크기를 추출하였고, 시험불안 감소 프로그램의 효과를 분석하기 위하여 총 115편의 논문에서 340개의 평균 효과크기를 추출하였다. 자료의 코딩 및 분석은 CMA 2를 활용하였다. 시험 불안 관련변인의 범주는 인지적 요인, 정의적 요인, 환경적 요인으로 분류 하였다. 분류된 변인들의 시험을안과의 직접적 상관 효과크기 뿐 아니라, 조절변수(하위 요인별, 성별, 학교 급별, 국내·외)별 로 시험불안과의 상관 효과크기 및 조절효과를 산출 비교 분석한 결과를 제시하였다. 시험불안 감 소 프로그램은 지역(국내·외) 성별, 학교 급별(초, 중, 고, 대), 구성 특성별(참여인원, 처치기간,처치회기, 주당처치회기, 회기시간), 내용별(인지중심, 행동중심,인지-행동중심, 학습기술, 인지행동-학습기술, 마음: 명상 등, 기타접근, 응악치료, 놀이치료 통찰치료)로 평균 효과크기 및 조절효과를 산출 비교 분석하였다. 이 연구는 최근까지 국내·외 시험불안 연구를 종합적으로 수집하여 시험불안과 여러 다른 변인들의 관계성을 다양하게 분석하고 시험불안으로 인해 어려움을 경험하는 학생들에게 가장 최선의 시험불안 감소 프로그램을 제공할 수 있도록 도웅을 제공하는 학문과 실천의 통합적 접근이라는 점에 큰 의의가 있다. The purpose of this study is to analyze and synthesize the relations between rest anxiety and related variables which have been dealt with, up until recently. at a domestic and international level, as well as the effects of Test Anxiety Decreasing Programs, To achieve this purpose, this study collected research based on test anxiety which had been carded out in 19 countries. In order to analyze the relations berween test anxiety and related variables, 3,293 correlation effect sizes were sampled from a total of 348 theses. To analyze the effects of Test Anxiety Decreasing Programs, 340 mean effect sizes were sampled from a total of Il5 theses. For the coding and analysis of such data, this study utilized CMA 2. Categories of variables that are related to test anxiety were classified as cognitive factors, affective factors, and environmental factors. The direct correlation effect sizes of the classified factors and test anxiety, as well as correlation effect size and the moderating effect of test anxiety that depends on each control variables (sub-factors, gender, school level, domestic and international) have been analyzed and presented. The average effect sizes and the moderating effect; of Test Anxiety Decreasing Programs were sampled, compared and analyzed on several levels: region(domestic and international), gender, school level (elementary, middle, high, university), constituent of program (number of participants, treatment period, treatment sessions, treatment sessions per week, session time), and content-specific (cognitive centered, behavior centered. cognitive- behavior centered, learning skills, cognitive behavioral and learning skills, mind such as meditating, and other approaches, music, play therapy, insight therapy). This study is meaningful as it synthetically collects studies on test anxiety. locally and abroad, which allows for a diverse analysis of the relations between test anxiety and several other variables. It is also significant as it is an integrated approach of theories and practices that can help to provide the best Test Anxiety Decreasing Programs to students who have difficulties with rest anxieties.

Ampelopsis japonica Makino extract (AE) inhibits the inflammatory reaction induced by pathogen-associated molecular patterns (PAMPs) in epidermal keratinocytes

( Mi Ra Choi ),( Jin Hyup Lee ),( Dae Kyoung Choi ),( Dong Il Kim ),( Hae Eul Lee ),( Myung Im ),( Young Lee ),( Chang Deok Kim ),( Young Joon Seo ),( Jeung Hoon Lee ) 대한피부과학회 2015 대한피부과학회 학술발표대회집 Vol.67 No.2

Background: Keratinocytes are the major cells inepidermis, providing barrier components such as cornified cells through the sophisticated differentiation process. In addition, keratinocytes exerts their role as the defense cells via activation of innate immunity. It has been knownthat pathogen-associated molecular patterns (PAMPs) including double-strand RNA and nucleotides can provoke inflammatory reaction in keratinocytes. Objectives: The aim of this study is to evaluate the effect of Ampelopsis japonica Makino extract (AE) on PAMPs-induced inflammatory reaction of keratinocytes. Methods: The effects of AE were determined using poly(I:C)-induced inflammation and imiquimod-induced psoriasiform dermatitis models. Results: In cultured keratinocytes, AE significantly inhibited poly(I:C)-induced expression of inflammatory cytokines, such as IL-1モ, IL-6, IL-8 and TNF-メ. AE significantly inhibited poly(I:C)-induced release of caspase-1 active form (p20), and down-regulated NF-リB signaling pathway. In imiquimod-induced psoriasiform dermatitis model, topical application of AE resulted in significant reduction of epidermal hyperplasia. Conclusion: These results suggest that AE may be a potential candidate for the treatment of skin inflammation.