Phytocomponent 4-hydroxy-3-methoxycinnamaldehyde ablates T-cell activation by targeting protein kinase C-theta and its downstream pathways

Akber Uroos; Na Bo-Ra; Ko You-Seung; Lee Hyun-Su; Kim Hye-Ran; Kwon Min-Sung; Park Zee-Yong; Choi Eun-Ju; Han Weon-Cheol; Lee Seung-Ho; Oh Hyun-Mee; Jun Chang-Duk

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Phytocomponent 4-hydroxy-3-methoxycinnamaldehyde ablates T-cell activation by targeting protein kinase C-theta and its downstream pathways

机译：植物共组4-羟基-3-甲氧基氨基丙醛通过靶向蛋白激酶C-θ及其下游途径烧蚀T细胞活化

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Autoreactive T-cell responses have a crucial role in the pathology and clinical course of autoimmune diseases. Therefore, controlling the activation of these cells is an important strategy for developing therapies and therapeutics. Here, we identified that 4-hydroxy-3-methoxycinnamaldehyde (4H3MC) has a therapeutic potential for T-cell activation by modulating protein kinase C-theta (PKC theta) and its downstream pathways. Pre- and post-treatment with 4H3MC prevented IL-2 release from human transformed and untransformed T cells at the micromolar concentrations without any cytotoxic effects, in fact more efficiently than its structural analogue 4-hydroxycinnamic acid-a previously reported T-cell inhibitor. In silica analysis showed that 4H3MC is a potential inhibitor of PKC isotypes, including PKC theta-a crucial PKC isotype in T cells. Consistently, 4H3MC significantly blocked PKC activity in vitro and also inhibited the phosphorylation of PKC theta in T cells. 4H3MC had no effect on TCR-mediated membrane-proximal-signalling events such as phosphorylation of Zap70. Instead, it attenuated the phosphorylation of mitogen-activated protein kinases (ERK and p38) and promoter activities of NF-kappa B, AP-1 and NFAT. Taken together, our results provide the evidences that 4H3MC may have curative potential as a novel immune modulator in a broad range of immunopathological disorders by modulating PKC theta activity. (C) 2015 Elsevier B.V. All rights reserved.

机译：自动反应性T细胞应答对自身免疫疾病的病理和临床进程具有至关重要的作用。因此，控制这些细胞的激活是开发治疗和治疗剂的重要策略。在此，我们认为4-羟基-3-甲氧基氨基醌（4H3MC）通过调节蛋白激酶C-THETA（PKCθ）及其下游途径具有T细胞活化的治疗潜力。用4H3MC预处理和后处理防止IL-2在微摩尔浓度下从人转化的和未转化的T细胞中释放而没有任何细胞毒性效应，实际上比其结构类似物4-羟基氨基氨基酸-A-A先前报道的T细胞抑制剂更有效。在二氧化硅分析中，表明，4H3MC是PKC同种型的潜在抑制剂，包括T细胞中的PKC THEA-A至关重要的PKC同种型。始终如一地，4H3MC在体外显着阻断了PKC活性，并且还抑制了T细胞中PKCθ的磷酸化。图4H3MC对TCR介导的膜 - 近端信号传导事件（如ZAP70的磷酸化）没有影响。相反，它抑制了丝裂原激活的蛋白激酶（ERK和P38）的磷酸化，NF-Kappa B，AP-1和NFAT的启动子活性。我们的结果通过调节PKCθ活性，我们的结果提供了4H3MC可能具有作为新型免疫病理障碍的新型免疫调节剂的疗效。（c）2015 Elsevier B.v.保留所有权利。

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来源
《International immunopharmacology》 |2015年第1期|共11页
作者
Akber Uroos; Na Bo-Ra; Ko You-Seung; Lee Hyun-Su; Kim Hye-Ran; Kwon Min-Sung; Park Zee-Yong; Choi Eun-Ju; Han Weon-Cheol; Lee Seung-Ho; Oh Hyun-Mee; Jun Chang-Duk;
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作者单位

Gwangu Inst Sci &

Technol Immune Synapse Res Ctr Sch Life Sci Kwangju 500712 South Korea;

Gwangu Inst Sci &

Technol Immune Synapse Res Ctr Sch Life Sci Kwangju 500712 South Korea;

Gwangu Inst Sci &

Technol Immune Synapse Res Ctr Sch Life Sci Kwangju 500712 South Korea;

Gwangu Inst Sci &

Technol Immune Synapse Res Ctr Sch Life Sci Kwangju 500712 South Korea;

Gwangu Inst Sci &

Technol Immune Synapse Res Ctr Sch Life Sci Kwangju 500712 South Korea;

Gwangu Inst Sci &

Technol Immune Synapse Res Ctr Sch Life Sci Kwangju 500712 South Korea;

Gwangu Inst Sci &

Technol Immune Synapse Res Ctr Sch Life Sci Kwangju 500712 South Korea;

Konkuk Univ Coll Nat Sci Div Sport Sci Chungbuk 380702 South Korea;

Wonkwang Univ Sch Med Dept Pathol Iksan 570749 Chonbuk South Korea;

Yeungnam Univ Coll Pharm Kyongsan 712749 South Korea;

KRIBB Bioind Proc Res Ctr Jeongeup 580185 South Korea;

Gwangu Inst Sci &

Technol Immune Synapse Res Ctr Sch Life Sci Kwangju 500712 South Korea;

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原文格式 PDF
正文语种 eng
中图分类药理学;
关键词
4-Hydroxy-3-methoxycinnamaldehyde; Immunosuppression; PKC theta; IL-2; T-cell activation; MAP kinase;

机译：4-羟基-3-甲氧基氨基醌;免疫抑制;PKC THETA;IL-2;T细胞活化;MAP激酶;

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专利

1. Phytocomponent 4-hydroxy-3-methoxycinnamaldehyde ablates T-cell activation by targeting protein kinase C-theta and its downstream pathways [J] . Akber Uroos, Na Bo-Ra, Ko You-Seung, International immunopharmacology . 2015,第1期

机译：植物共组4-羟基-3-甲氧基氨基丙醛通过靶向蛋白激酶C-θ及其下游途径烧蚀T细胞活化
2. Phytocomponent p-Hydroxycinnamic acid inhibits T-cell activation by modulation of protein kinase C-θ-dependent pathway [J] . LeeH.-S., KimY.-D., NaB.-R., International immunopharmacology . 2012,第1期

机译：植物成分对羟基肉桂酸可通过调节蛋白激酶C-θ依赖性途径抑制T细胞活化
3. Effects of inhibitors of vascular endothelial growth factor receptor 2 and downstream pathways of receptor tyrosine kinases involving phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin or mitogen-activated protein kinase in canine hemangiosarcoma cell lines [J] . Mami Adachi, Yuki Hoshino, Yusuke Izumi, Canadian Journal of Veterinary Research . 2016,第3期

机译：血管内皮细胞生长因子受体2抑制剂及其受体酪氨酸激酶下游途径对雷帕霉素或丝裂原活化蛋白激酶的磷脂酰肌醇3-激酶/ Akt /哺乳动物靶标的影响
4. Identification of potential Mitogen Activated Protein Kinase effectors in T-cell Receptor signaling by Phosphoproteomics [C] . Viveka Mayya, Deborah H. Lundgren, Sun-Il Hwang, ASMS Conference on Mass Spectrometry and Allied Topics . 2007

机译：磷蛋白蛋白酶菌鉴定磷蛋白受体信号传导潜在丝裂丝瘤活性蛋白激酶作用
5. Protein kinase C regulation of surfactant protein B expression: Role of mitogen activated protein kinase pathways. [D] . Ravindranathan, Preethi. 2008

机译：表面活性蛋白B表达的蛋白激酶C调节：促分裂原活化蛋白激酶途径的作用。
6. Mammalian mitogen-activated protein kinase kinase kinase (MEKK) can function in a yeast mitogen-activated protein kinase pathway downstream of protein kinase C. [O] . K J Blumer, G L Johnson, C A Lange-Carter 1994

机译：哺乳动物有丝分裂原激活的蛋白激酶激酶激酶（MEKK）可以在蛋白激酶C下游的酵母有丝分裂原激活的蛋白激酶途径中发挥作用。
7. Mammalian mitogen-activated protein kinase kinase kinase (MEKK) can function in a yeast mitogen-activated protein kinase pathway downstream of protein kinase C. [O] . Blumer, K J, Johnson, G L, Lange-Carter, C A 1994

机译：哺乳动物有丝分裂原激活的蛋白激酶激酶激酶（MEKK）可以在蛋白激酶C下游的酵母有丝分裂原激活的蛋白激酶途径中发挥作用。

Phytocomponent 4-hydroxy-3-methoxycinnamaldehyde ablates T-cell activation by targeting protein kinase C-theta and its downstream pathways

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