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      Resveratrol의 CD4+ T 세포 활성과 분화 억제 효과 = Resveratrol Suppresses CD4+ T Cell Activation and Differentiation in vitro

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      https://www.riss.kr/link?id=A103848312

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      다국어 초록 (Multilingual Abstract)

      Resveratrol is a naturally occurring stilbene which is safe and well-described compound with a potent anti-inflammatory activity. Recent studies suggested that resveratrol suppressed various inflammation mediated diseases such as asthma, chronic colit...

      Resveratrol is a naturally occurring stilbene which is safe and well-described compound with a potent anti-inflammatory activity. Recent studies suggested that resveratrol suppressed various inflammation mediated diseases such as asthma, chronic colitis, rheumatoid arthritis, and type 1 diabetes. These studies indicated that resveratrol might directly modulate CD4 + helper T cells (Th cells)-mediated immune responses. However, it is not fully elucidated whether resveratrol directly regulates CD4 + Th cell activation and differentiation. In the present study, CD4 + Th cells were purified from C57BL/6 and treated with various concentrations of resveratrol. We found that resveratrol directly suppressed CD4 + Th cells activation, leading to a defect in T cell proliferation. When CD4 + Th cells were treated with resveratrol, cytokine production was also significantly reduced in a dose dependent manner. In accordance with these results, resveratrol even inhibited CD4 + Th cells differentiation into Th1, Th2 or Th17, which produces IFN-γ, IL-4 or IL-17 respectively. We also found that resveratrol could induce apoptosis of CD4 + T cells at a high concentration. Our data demonstrated that resveratrol inhibited directly CD4 + Th cells activation and differentiation. It suggests that resveratrol could be an efficient therapeutic strategy for autoimmune diseases in which CD4 + Th cells play a critical role.

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      국문 초록 (Abstract)

      Resveratrol은 천연 stilbene으로 안전성 있는 항염증 활성을 가진 화합물로 알려져 있다. 최근의 연구들에서 resveratrol이 천식, 만성 대장염, 류마티스성 관절염과 같이 염증에 의해발생하는 다양...

      Resveratrol은 천연 stilbene으로 안전성 있는 항염증 활성을 가진 화합물로 알려져 있다. 최근의 연구들에서 resveratrol이 천식, 만성 대장염, 류마티스성 관절염과 같이 염증에 의해발생하는 다양한 질병을 억제한다고 보고되었다. 이러한 연구들은 resveratrol이 CD4+ helper T cells (Th cells)에 의한 면역반응을 조절할 것이라고 제시하였다. 그러나 resveratrol이 직접적으로 Th cells의 활성화와 분화를 조절하는지 완전히 밝혀지지 않았다. C57BL/6에서 Th cells을 분리하여 다양한 농도의resveratrol을 세포에 처리하였다. 본 연구에서는 resveratrol이 직접적으로 Th cells의 활성화와 증식을 억제하는 것을 확인하였다. Th cells에 resveratrol을 처리하였을 때 IFN-γ, IL-4,IL-17 사이토카인 생성이 농도에 따라 유의하게 감소하였고 또한 Th cells이 이러한 사이토카인들을 분비하는 Th1과 Th2과Th17으로 분화되는 것이 억제되었다. 그리고 고농도의 resveratrol이 Th cells의 세포사멸을 유도하는 것으로 확인되었다. 본 연구에서는 resveratrol이 Th cells의 활성화와 분화를 직접적으로억제하는 것을 확인하였으며, 이는 resveratrol이 CD4+ Thcells에 의해 발생되는 자가면역질환의 효과적인 치료법이 될수 있을 것이라고 제시한다.

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      참고문헌 (Reference)

      1 Mosmann, T.R., "Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins" 136 : 2348-2357, 1986

      2 Crome, S.Q., "Translational mini-review series on Th17 cells: Function and regulation of human T helper 17 cells in health and disease" 159 : 109-119, 2010

      3 Epstein, F.H., "The role of T-cell costimulatory activation pathways in transplant rejection" 338 : 1813-1821, 1998

      4 Pace-Asciak, C.R., "The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: Implications for protection against coronary heart disease" 235 : 207-219, 1995

      5 Takaoka, M., "The phenolic substances of white hellebore (Veratrum grandiflorum Loes. Fill). V. Synthesis of resveratrol (3, 5, 4-trioxystilbene) and its derivatives" 61 : 1067-1069, 1940

      6 Akbar, A.N., "The dynamic co-evolution of memory and regulatory CD4+ T cells in the periphery" 7 : 231-237, 2007

      7 Chan, M.M., "Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway" 60 : 1539-1548, 2000

      8 Tsai, S.H., "Suppression of nitric oxide synthase and the down-regulation of the activation of NFkappaB in macrophages by resveratrol" 126 : 673-680, 1999

      9 Kaeberlein, M., "Substratespecific Activation of Sirtuins by Resveratrol" 280 : 17038-17045, 2005

      10 Howitz, K.T., "Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan" 425 : 191-196, 2003

      1 Mosmann, T.R., "Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins" 136 : 2348-2357, 1986

      2 Crome, S.Q., "Translational mini-review series on Th17 cells: Function and regulation of human T helper 17 cells in health and disease" 159 : 109-119, 2010

      3 Epstein, F.H., "The role of T-cell costimulatory activation pathways in transplant rejection" 338 : 1813-1821, 1998

      4 Pace-Asciak, C.R., "The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: Implications for protection against coronary heart disease" 235 : 207-219, 1995

      5 Takaoka, M., "The phenolic substances of white hellebore (Veratrum grandiflorum Loes. Fill). V. Synthesis of resveratrol (3, 5, 4-trioxystilbene) and its derivatives" 61 : 1067-1069, 1940

      6 Akbar, A.N., "The dynamic co-evolution of memory and regulatory CD4+ T cells in the periphery" 7 : 231-237, 2007

      7 Chan, M.M., "Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway" 60 : 1539-1548, 2000

      8 Tsai, S.H., "Suppression of nitric oxide synthase and the down-regulation of the activation of NFkappaB in macrophages by resveratrol" 126 : 673-680, 1999

      9 Kaeberlein, M., "Substratespecific Activation of Sirtuins by Resveratrol" 280 : 17038-17045, 2005

      10 Howitz, K.T., "Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan" 425 : 191-196, 2003

      11 Leibiger, I.B., "Sirt1: a metabolic master switch that modulates lifespan" 12 : 34-36, 2006

      12 Wang, Q., "Resveratrol protects against global cerebral ischemic injury in gerbils" 958 : 439-447, 2002

      13 Xuzhu, G., "Resveratrol modulates murine collagen-induced arthritis by inhibiting Th17 and B-cell function" 71 : 129-135, 2012

      14 Moreno, J.J., "Resveratrol modulates arachidonic acid release, prostaglandin synthesis, and 3T6 fibroblast growth" 294 : 333-338, 2000

      15 Ren, Z., "Resveratrol inhibits NF-kB signaling through suppression of p65 and IkappaB kinase activities" 68 : 689-694, 2013

      16 Liu, P., "Resveratrol induces apoptosis of pancreatic cancers cells by inhibiting miR-21 regulation of BCL-2 expression" 15 : 741-746, 2013

      17 Shimizu, T., "Resveratrol induces apoptosis of human malignant B cells by activation of caspase-3 and p38 MAP kinase pathways" 71 : 742-750, 2006

      18 Rayalam, S., "Resveratrol induces apoptosis and inhibits adipogenesis in 3T3-L1 adipocytes" 22 : 1367-1371, 2008

      19 Ge, J., "Resveratrol induces apoptosis and autophagy in T-cell acute lymphoblastic leukemia cells by inhibiting Akt/mTOR and activating p38-MAPK" 26 : 902-911, 2013

      20 Marchal, J., "Resveratrol in mammals: effects on aging biomarkers, age-related diseases, and life span" 1290 : 67-73, 2013

      21 Estrov, Z., "Resveratrol blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells" 102 : 987-995, 2003

      22 Aich, J., "Resveratrol attenuates experimental allergic asthma in mice by restoring inositol polyphosphate 4 phosphatase (INPP4A)" 14 : 438-443, 2012

      23 Youn, J., "Resveratrol and piceatannol inhibit iNOS expression and NF-kappaB activation in dextran sulfate sodium-induced mouse colitis" 61 : 847-854, 2009

      24 Walker, J., "Resveratrol and its metabolites inhibit pro-inflammatory effects of lipopolysaccharides in U-937 macrophages in plasma-representative concentrations" 5 : 74-84, 2014

      25 Abdallah, D.M., "Resveratrol abrogates adhesion molecules and protects against TNBS-induced ulcerative colitis in rats" 89 : 811-818, 2011

      26 Zou, T., "Resveratrol Inhibits CD4+ T cell activation by enhancing the expression and activity of Sirt1" 8 : e75139-, 2013

      27 Romagnani, S., "Regulation of the development of type 2 T-helper cells in allergy" 6 : 838-846, 1994

      28 Chung, S., "Regulation of SIRT1 in cellular functions: role of polyphenols" 501 : 79-90, 2010

      29 Sinha, K., "Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats" 71 : 655-665, 2002

      30 Peck, A., "Plasticity of T-cell phenotype and function: the T helper type 17 example" 129 : 147-153, 2010

      31 Sakaguchi, S., "Naturally arising Foxp3-expressing CD25+ CD4+ regulatory T cells in immunological tolerance to self and non-self" 6 : 345-352, 2005

      32 Kundu, J.K., "Molecular basis of chemoprevention by resveratrol: NF-kappaB and AP-1 as potential targets" 555 : 65-80, 2004

      33 Hirahara, K., "Mechanisms underlying helper T-cell plasticity: implications for immune-mediated disease" 131 : 1276-1287, 2013

      34 Borra, M.T., "Mechanism of Human SIRT1 Activation by Resveratrol" 280 : 17187-17195, 2005

      35 Ariel, A., "Macrophages in inflammation and its resolution" 3 : 324-, 2012

      36 Zhong, M., "Inhibitory effect of resveratrol on interleukin 6 release by stimulated peritoneal macrophages of mice" 6 : 79-84, 1999

      37 Qureshi, A.A., "Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor" 11 : 76-, 2012

      38 Frankel, E.N., "Inhibition of human LDL oxidation by resveratrol" 341 : 1103-1104, 1993

      39 Wu, S.L., "Immunosuppression by combined use of cyclosporine and resveratrol in a rat liver transplantation model" 37 : 2354-2359, 2005

      40 Hall, A.M., "Helper T cells point the way to specific immunotherapy for autoimmune disease" 9 : 159-166, 2009

      41 Tennen, R.I., "Finding a target for resveratrol" 148 : 387-389, 2012

      42 Leiro, J., "Effects of cis-resveratrol on inflammatory murine macrophages: antioxidant activity and down-regulation of inflammatory genes" 75 : 1156-1165, 2004

      43 Nonomura, S., "Chemical Constituents Of Polygonaceous Plants. I. Studies on the components of KO-J O-KON. (Polygonum cuspidatum SIEB. ET ZUCC.)" 83 : 988-990, 1963

      44 Bradamante, S., "Cardiovascular protective effects of resveratrol" 22 : 169-188, 2004

      45 Jang, M., "Cancer chemopreventive activity of resveratrol, a natural product derived from grapes" 275 : 218-220, 1997

      46 Asano, M., "Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation" 184 : 387-396, 1996

      47 Svajger, U., "Anti-inflammatory effects of resveratrol and its potential use in therapy of immune-mediated diseases" 31 : 202-222, 2012

      48 Chen, X., "Anti-inflammatory effect of resveratrol on adjuvant arthritis rats with abnormal immunological function via the reduction of cyclooxygenase-2 and prostaglandin E2" 9 : 2592-2598, 2014

      49 Lee, M., "Anti-inflammatory and anti-asthmatic effects of resveratrol, a polyphenolic stilbene, in a mouse model of allergic asthma" 9 : 418-424, 2009

      50 Donmez, G., "Aging and disease: connections to sirtuins" 9 : 285-290, 2010

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