2013 International Conference & Exhibition on Nutraceuticals and Functional Foods

 

11月5日〜11月9日  台北、台湾にて

リン博士による発表

 

複数の柑橘果皮を調合したエキスが免疫樹状細胞の機能を弱め、

アレルギー性接触過敏症を減少させる

 

<要旨内容>

柑橘フルーツの皮から調合されて出来た商品、ゴールド化粧水は、抗腫瘍、抗酸化や抗炎症作用などのような多くの薬理作用を持っている。今回の我々の研究ではLPSリポ多糖類で刺激させてマウスの骨髄から発生させた樹状細胞発育(骨髄系樹状細胞)と機能に関してゴールドの免疫調節作用を調べた。結果、ゴールドは炎症前駆体サイトカインとケモカインの発現を量依存的に顕著に抑制した。更にゴールドでの処置はMHCや共起刺激分子(アクセサリー細胞の膜結合性あるいは、分泌性産物でシグナル伝達が必要なもの)の発現を抑制。これは抗原を取り込む作用に影響を与えているとみなされる。また、LPS刺激により発生させた樹状細胞のアロ反応性T細胞活性化作用を減少させた。更に動物実験でのゴールドの経口投与では、2,4-ジニトロフルオロベンゼンによる接触過敏症(CHS)を低下させた。一貫して分子検査でもゴールドはLPS刺激により発生させたMAPK-ERK分裂促進因子活性化蛋白質キナーゼ、p38リン酸化、核内転写因子NF-κB p65を減少させた。これらから今回の発見はゴールドの免疫薬理学に対する役割に新しい見識をもたらすものであり、樹状細胞介入による慢性の炎症性障害や自己免疫疾患症を治療できると考えられる。

 

*樹状細胞:抗原提示細胞として機能する免疫細胞の一種であり哺乳類の免疫系の一部を担う。抗原提示細胞とは自分が取り込んだ抗原を他の免疫系の細胞に伝える役割を持つ。抗原を取り込むと樹状細胞は活性化され、脾臓などのリンパ器官に移動する。リンパ器官では取り込んだ抗原に特異的なT細胞やB細胞を活性化する。樹状細胞は発現している表面抗原分子により様々なサブユニットに分類される。)

*ケモカイン:G蛋白質共役受容体を介してその作用を発現する塩基性蛋白質であり、サイトカインの一群。白血球などの郵送を引き起こし炎症の形成に関与。これまでに50種類以上のケモカインが同定されている。

MHC:主要組織適合遺伝子複合体(免疫担当細胞間の認識機構・組織特異抗原や移植適合性をつかさどる細胞表面糖タンパクをコードする遺伝子領域で蜜に連鎖して一定の染色体領域に存在する。マウスではH-2、ヒトではHLA複合体よりなる。

 

リン博士は下記についても文献の用意をしているとの事です。

1)          肺癌に対するゴールドの抗腫瘍作用:10%でステージ2への進行を止め、自家融解(細胞内の損傷を受けた細胞小器官の処理と分離)を起こす。

2)          ゴールド経口投与による乾癬症における免疫薬理学作用

 

 

Formulated extract from multiple citrus peels impairs immune dendritic cells functions and attenuates allergic contact hypersentivity

 

Gold lotion (GL), a formulated product made from the peels of citrus fruits, has many pharmacological activities, such as anti-tumor, antioxidant, and anti-inflammatory activities. In this study, we examine the immunomodulatory effect of GL on lipopolysacchride (LPS) stimulated mouse bone marrow-derived DCs maturation and function. Our experimental results show that GL significantly inhibited the pro-inflammatory cytokines and chemokine expression in LPS-induced DCs in a dose dependent manner. In addition, GL treatment led to inhibit the expression of of MHC and costimulatory molecules, influence the ability to take up antigen and attenuated allo-T cell activating ability of LPS stimaultaed DCs. Furthermore, oral administration of GL attenuates the 2,4-Dinitro-1-fluorobenzene induced contact hypersensitivit (CHS) in vivo. Consequently, molecular studies showed that GL decrease LPS-induced MAPK-ERK, p38 phosphrylation and nuclear translocation of NF-κB p65. Taken together, these findings provide new insight into the immunopharmacological role of GL and used to treat DC mediated-chronic inflammatory disorders or autoimmune diseases.

 

 

 

Introduction of Researchers & Universities

Shiming Li1,1a, Yi-Chin Lin2, Chi-Tang Ho1, Ping-Yi Lin3, Michiko Suzawa4, Hsin-Chieh Wang2, Ching-Liang Chu5, Der-Yuan Chen2,6, Chi-Chen Lin*2,6,7,8,

 

1Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA

1aColleage of Chemistry and Chemical Engineering, Huanggang Normal University, Hubei, 438000, China

2Institute of Biomedical Science, National Chung-Hsing University, Taichung, Taiwan

3Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan

4Miyauchi Citrus Research Center, Shigoka-Machi, Takasaki, Gunma, 370-0845, Japan

5Graduate Institutes of Immunology, College of Medicine, National Taiwan University, Taipei 100, Taiwan

6Department of Medical Research and Education, Taichung Veterans General Hospital, Taichung, Taiwan, Republic of China.

7Division of Chest Medicine, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan

8Rong Hsing Research Center for Translational Medicine, National Chung Hsing University

 

*To whom correspondence should be addressed:

Dr. Chi-Chen Lin, Institute of Biomedical Sciences, College of Life Science, National Chung Hsing University, Taichung, Taiwan FAX: +886-4-23592705, E-Mail: lincc@dragon.nchu.edu.tw

 

 

 

References

[1] Hakim IA, Harris RB, Ritenbaugh C. Citrus peel use is associated with reduced risk of squamous cell carcinoma of the skin. Nutrition and cancer 2000;37: 161-168.

[2] Chutia M, Deka Bhuyan P, Pathak MG, Sarma TC, Boruah P. Antifungal activity and chemical composition of Citrus reticulata Blanco essential oil against phytopathogens from North East India. LWT—Food Science and Technology 2009;42:777–780.

[3] Sawamura M, Thi Minh Tu N, Onishi Y, Ogawa E, Choi HS. Characteristic odor components of Citrus reticulata Blanco (ponkan) cold-pressed oil.Bioscience, Biotechnology and Biochemistry 2004;68:1690–1697.

[4] Espina L, Somolinos M, Lorán S, Conchello P, García D, Pagán R. Chemical composition of commercial citrus fruit essential oils and evaluation of their antimicrobial activity acting alone or in combined processes. Food Control 2011;22:896–902.

[5] Ho, SC. and Lin CC. Investigation of heat treating conditions for enhancing the anti-inflammatory activity of citrus fruit (Citrus reticulata) peels. Journal of agricultural and food chemistr. 2008;56:7976-7982.

[6] Epifano F, Genovese S, Curini M. Auraptene: phytochemical and pharmacological properties. Phytochemistry Research Progress 2008;145-62.

[7] Upadhyay RK, Dwivedi P, Ahmad S. Screening of antibacterial activity of six plant essential oils against pathogenic bacterial strains. Asian J Med Sci  2010;2: 152-8.

[8] Yang EJ, Kim SS, Moon JY, Oh T-H, Baik JS, Lee NH, et al. Inhibitory effects of Fortunella japonica var. margarita and Citrus sunki essential oils on nitric oxide production and skin pathogens. Acta microbiologica et immunologica Hungarica. 2010;57:15-27.

[9] Yi E, Yoo ES. A novel bioactive fabric dyed with unripe Citrus grandis Osbeck extract part 1: dyeing properties and antimicrobial activity on cotton knit fabrics. Textile Research Journal 2010;80:2117-23.

[10] Benavente-Garcia O, Castillo J. Update on uses and properties of citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity. Journal of Agricultural and Food Chemistr. 2008;56:6185-205.

[11] Kurowska EM, Manthey JA, Casaschi A, Theriault AG. Modulation of HepG2 cell net apolipoprotein B secretion by the citrus polymethoxyflavone, tangeretin. Lipids 2004;39:143-51.

[12] Manthey JA, Guthrie N, Grohmann K. Biological properties of citrus flavonoids pertaining to cancer and inflammation. Current Medicinal Chemistry 2001;8: 135-53.

[13] Miyazawa M, Okuno Y, Fukuyama M, Nakamura S-i, Kosaka H. Antimutagenic activity of polymethoxyflavonoids from Citrus aurantium. Journal of Agricultural and Food Chemistry 1999:47:5239-44.

[14] Roza JM, Xian-Liu Z, Guthrie N. Effect of citrus flavonoids and tocotrienols on serum cholesterol levels in hypercholesterolemic subjects. Alternative Therapies in Health and Medicine 2007;13:44.

[15] Xiao H, Yang CS, Li S, Jin H, Ho CT, Patel T. Monodemethylated polymethoxyflavones from sweet orange (Citrus sinensis) peel inhibit growth of human lung cancer cells by apoptosis. Molecular nutrition & food research 2009; 53:398-406.

[16] Lai CS, Li S, Liu CB, Miyauchi Y, Suzawa M, Ho CT, Pan MH. Effective suppression of azoxymethane-induced aberrant crypt foci formation in mice with citrus peel flavonoids. Molecular nutrition & food research 2013;57:551-5.

[17] Pan MH, Li S, Lai CS, Miyauchi Y, Suzawa M, Ho CT. Inhibition of citrus flavonoids on 12-O-tetradecanoylphorbol 13-acetate-induced skin inflammation and tumorigenesis in mice. Food Science and Human Wellness 2012;1:65–73.

[18] Lai CS, Li S, Miyauchi Y, Suzawa M, Ho CT, Pan MH. Potent anti-cancer effects of citrus peel flavonoids in human prostate xenograft tumors. Food Funct 2013;4:944-9.

 

[19] Etoh T, Kim YP, Hayashi M, Suzawa M, Li S, Ho CT, and Komiyama K. Inhibitory effect of a formulated extract from multiple citrus peels on LPS-induced inflammation in RAW 246.7 macrophages. Functional Foods in Health and Disease 2013;3:242-253.

[20] Granucci F, Zanoni I, Ricciardi-Castagnoli P. Central role of dendritic cells in the regulation and deregulation of immune responses. Cell Mol Life Sci 2008;65: 1683-97.

[21] Steinman RM, Hemmi H. Dendritic cells: translating innate to adaptive immunity. Current Topics in Microbiology and Immunology 2006;311:17–58.

[22] Hivroz C, Chemin K, Tourret M, Bohineust A. Crosstalk between T lymphocytes and dendritic cells. Crit Rev Immunol 2012;32:139-155.

[23] Förster R, Braun A, Worbs T. Lymph node homing of T cells and dendritic cells via afferent lymphatics. Trends Immunol 2012;33:271-280.

[24] P. Hubert, N. Jacobs, J. H. Caberg, J. Boniver, and P. Delvenne, “The cross-talk between dendritic and regulatory T cells: good or evil?” Journal of Leukocyte Biology 2007;82:781–794.

[25] Chen DY, Song PS, Hong JS, Chu CL, Pan IH, Chen YM, Lin CH, Lin SH, Lin CC. Dextromethorphan inhibits activations and functions in dendritic cells. Clin Dev Immunol 2013;125643.

[26] Lin CC, Yu YL, Shih CC, Liu KJ, Ou KL, Hong LZ, Chen JD, Chu CL. A novel adjuvant Ling Zhi-8 enhances the efficacy of DNA cancer vaccine by activating dendritic cells. Cancer Immunol Immunother 2011;60:1019-27.

[27] Huang RY, Yu YL, Cheng WC, OuYang CN, Fu E, Chu CL. Immunosuppressive effect of quercetin on dendritic cell activation and function. J Immuno. 2010;184:6815-21.

[28] Kim GY, Han MG, Song YS et al. Proteoglycan isolated from Phellinus linteus induces toll-like receptors 2- and 4- mediated maturation of murine dendritic cells via activation of ERK, p38, and NF-κB. Biol Pharm Buli 2004;27:1656–1662.

 

[29] Rescigno M, Martino M, Sutherland CL, Gold MR, Ricciardi- Castagnoli P. Dendritic cell survival and maturation are regulated by different signaling pathways. J Exp Med 1998;188:2175–2180.

[30] Yokoi S, Niizeki H, Iida H, Asada H, Miyagawa S. Adjuvant effect of lipopolysaccharide on the induction of contact hypersensitivity to haptens in mice. J Dermatol Sci 2009;53:120-128.

[31] Geldart T, Illidge T. Anti-CD 40 monoclonal antibody. Leuk Lymph 2005;46: 1105–13.

[32] Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 2002;2: 116–126.

[33] Teague TK, Marrack P, Kappler JW, Vella AT. IL-6 rescues resting mouse T cells from apoptosis. J Immunol 1997;158:5791–5796.

[34] Dienz O, Rincon M. The effects of IL-6 on CD4 T cell responses. Clin Immunol. 2009;130:27-33.

[35] Yoo JK, Cho JH, Lee SW, Sung YC. IL-12 provides proliferation and survival signals to murine CD4+ T cells through phosphatidylinositol 3-kinase/Akt signaling pathway. J Immunol 2002;169:3637-43.

[36] Estaquier, J., T. Idziorek, W. Zou, D. Emilie, C. M. Farber, J. M. Bourez, J. C. Ameisen. T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons. J. Exp. Med 1995;182:1759.

[37] Marth, T., M. Zeitz, B. R. Ludviksson, W. Strober, B. L. Kelsall. Extinction of IL-12 signaling promotes Fas-mediated apoptosis of antigen-specific T cells. J. Immunol 1999;162:7233.

[38] Gasparini C, Feldmann M. NF-κB as a target for modulating inflammatory responses. Curr Pharm Des 2012;18:5735-5745.

 

[39] Rescigno M, Martino M, Sutherland CL, Gold MR, Ricciardi- Castagnoli P. Dendritic cell survival and maturation are regulated by different signaling pathways. J Exp Med 1998;188:2175–2180.

[40] Kim GY, Han MG, Song YS et al. Proteoglycan isolated from Phellinus linteus induces toll-like receptors 2- and 4- mediated maturation of murine dendritic cells via activation of ERK, p38, and NF-κB. Biol Pharm Bull 2004;27:1656–1662.

[41] Wang J, Wang X, Hussain S, et al. Distinct roles of different NF-kappa B subunits in regulating inflammatory and T cell stimulatory gene expression in dendritic cells. J Immunol 2007;178:6777-6788.

[42] Kidd P. Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Altern Med Rev 2003;8:223–46.

[43] Gately MK, Renzetti LM, Magram J, et al. The interleukin-12/interleukin-12-receptor system : role in normal and pathologic immune responses. Annu Rev Immunol 1998;16:495-521.

[44] Wang B, Feliciani C, Freed I, Cai Q, Sauder DN. Insights into molecular mechanisms of contact hypersensitivity gained from gene knockout studies. J Leukoc Biol 2001;70:185–191.

[45] Granucci F, Zanoni I. Role of Toll like receptor-activated dendritic cells in the development of autoimmunity. Front Biosci 2008;13:4817-26.

[46] Barber GN., Innate immune DNA sensing pathways: STING, AIMII and the regulation of interferon production and inflammatory responses. Curr Opin Immunol 2011;23:10-20.