山苦瓜影響調節型T細胞進而調節腸道免疫之研究

呂學耘

doi:10.6342/NTU201601903

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山苦瓜影响调节型T细胞进而调节肠道免疫之研究

Study on the effect of wild bitter melon on regulatory T cells and further modulation of intestinal immune system

吕学耘 , 博士　　导师：林璧凤　　

繁体中文 DOI： 10.6342/NTU201601903

苦瓜；调节型T细胞；肠道免疫；发炎性肠道疾病；肠系膜淋巴结； bitter melon ； regulatory T cell ； intestinal immune system ； inflammatory bowel disease ； mesenteric lymph nodes

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摘要 │ 参考文献 (229) │ 国际计量

摘要〈TOP〉

慢性发炎和免疫失调与许多疾病的发生相关，包括胰岛素抗性、过敏与发炎性大肠疾病等，调节型T细胞 (Regulatory T cells, Treg)具有抗发炎与调节免疫的作用。山苦瓜 (wild bitter melon, WBM) 已被应用於改善胰岛素抗性，但免疫相关的研究仍少，因此本研究探讨山苦瓜对肠道免疫系统及调节型T细胞的影响。以高油饮食诱导肥胖的C57BL/6J小鼠，探讨山苦瓜是否透过抗发炎与免疫调节改善胰岛素抗性，结果喂食含5％山苦瓜冻乾粉末饲料12周，降低小鼠禁食血糖和血脂，改善胰岛素抗性，降低脂肪组织SVF (stromal vascular fraction) M1/M2的比例与CD4+ T细胞的数量。同时，山苦瓜增加肠系膜淋巴结 (mesenteric lymph nodes, MLN) 的CD4+CD25+Foxp3+ Treg比率与数量。以喂食Foxp3-EGFP小鼠山苦瓜验证山苦瓜对肠道免疫及Treg的影响，结果显示山苦瓜显着增加Foxp3-EGFP小鼠MLN的CD4+CD25+Foxp3+ Treg比率与数量，且MLN与皮耶氏体细胞分泌较高的IL-10及TGF-β，再次显示山苦瓜具有促进肠道Treg免疫之作用。
为探讨山苦瓜各萃物对增加调节型T细胞的分化潜力与机制，以山苦瓜各萃物添加於初代脾脏、MLN、CD4+ T与树突细胞培养试验培养液中。结果山苦瓜M-Res与BuE萃物可促进初代脾脏细胞IL-10和TGF-β分泌，透过aryl hydrocarbon receptor (AhR) 增加CD4+ T细胞分化为Foxp3+ Treg。而WE萃物促进初代树突细胞IL-10分泌，且WE萃物培养後的树突细胞可增加CD4+ T细胞分化为 IL-10+ T细胞与Foxp3+ Treg。实验续以BuE萃物纯化分离并监定活性成份，结果发现增加CD4+ T细胞分化为Foxp3+ Treg成份之一为tryptophan。
最後，以dextran sulfate sodium (DSS) 诱发肠炎小鼠模式，验证山苦瓜与tryptophan是否透过增加Treg，减缓肠道发炎反应。实验於DSS诱发肠炎前喂食小鼠含5%山苦瓜冻乾粉饲料或0.5% tryptophan饲料共2周或6周，结果山苦瓜能显着增加MLN内Foxp3+ Treg及大肠Foxp3 mRNA基因表现量，并降低大肠组织IL-6与IL-17，增加IL-10含量，减缓DSS诱发小鼠体重流失、疾病指数与肠道缩短现象。2周补充tryptophan显着降低大肠组织IL-6含量，减缓小鼠疾病指数。大肠组织TNF-α、IL-6、IL-1β、IL-17含量以及疾病指数，皆与Foxp3 mRNA表现量呈现显着负相关，显示山苦瓜透过增加肠道中Treg，降低肠道发炎反应，减缓DSS诱发肠炎小鼠疾病指数。
综合上述结果，山苦瓜具有促进小鼠肠道调节型T细胞免疫作用，减缓DSS诱发肠炎小鼠肠道发炎。山苦瓜促进调节型T细胞免疫的活性萃物包含M-Res、BuE和WE萃物，可能的机制为活化AhR，促进Foxp3的表现；增加CD103+ 树突细胞比率及IL-10分泌，促进Foxp3+ Treg与IL-10+CD4+ T细胞分化。显示山苦瓜具有抗发炎与免疫调节之功效，维持肠道免疫平衡，可应用於预防及减缓发炎性肠道疾病，做为肠道保健之蔬果，与开发为肠道保健相关食品的潜力。

并列摘要〈TOP〉

Chronic inflammation and immune disorder are associated with insulin resistance, allergy, inflammatory bowel disease, etc. Regulatory T lymphocytes (Treg) suppress a variety of inflammatory and pathological immune responses. Wild bitter melon (WBM) has been demonstrated to improve the insulin resistance, but its effect on immune is still unclear. Therefore, the aim of this study is to investigate the effect of WBM on the intestinal immune system and Treg development. First, to investigate the improvement in insulin resistance of wild bitter melon is involved with its immune modulatory effects. High-fat diet-induced obese C57BL/6J mice were fed the diet containing 5% WBM powder for 12 weeks. The results showed that WBM treatment reduced fasting glucose and triglyceride in the serum, and improved insulin resistance. WBM reduced the M1/M2 ratio and CD4+ T cells infiltration in stromal vascular fraction (SVF). Moreover, WBM increased the percentage of CD4+Foxp3+ Treg in mesenteric lymph nodes (MLN). 
To confirm the effects of WBM on intestinal immune system and Foxp3+ Treg cells population, Foxp3-EGFP mice co-expressing EGFP and Foxp3 in Treg were fed WBM experimental diet. The results showed that WBM also increased the percentage of CD4+ Foxp3+ Treg in MLN and interleukin (IL)-10 and TGF (transforming growth factor)-β secretion by ConA-stimulated Peyer’s patches and MLN cells. These results suggested that WBM could enhance the Foxp3+ Treg development in the intestinal immune system. 
The bioactive compounds of WBM and mechanisms of promoting the development of Treg were investigated by using the primary spleen cells, MLN cells, CD4+ T cells and bone marrow derived dendritic cells (BMDC) culture in vitro. The results showed that M-Res and BuE extract of WBM increased IL-10 and TGF-β secretion by splenocytes and promoted the development of Foxp3+ Treg through the aryl hydrocarbon receptor (AhR) pathway. WE extract increased IL-10 secretion by BMDC and promoted CD4+ T cells differentiate into IL-10+ T cells and Foxp3+ T cells in CD4+ T cells cocultured with WE pretreated BMDC. Moreover, tryptophan is the bioactive compound from BuE extract was found that increase Foxp3+ Treg development in vitro.
The anti-inflammatory and immunomodulatory effects of WBM and tryptophan on inflammatory bowel disease were investigated by using dextran sodium sulphate (DSS)- induced colitis murine model. A diet containing 5% WBM or 0.5% tryptophan was administered to mice for 2 or 6 weeks and then gave 7 days DSS treatment. WBM intake significantly improved weight loss, disease activity index and colon shortening.  Colonic cytokine IL-6 and IL-1β were significantly decreased, and the anti-inflammatory cytokine IL-10 was increased in WBM-fed mice. The mRNA expression of TGF-β and Foxp3 in colon, and Foxp3+ Treg cell population in the MLN were also significantly higher in the WBM group. Tryptophan supplement ameliorated disease activity index and reduced the colonic IL-6 levels. The significantly negative correlation between Foxp3 mRNA expression and pro-inflammatory cytokines in colon is in accordance with the critical role of Treg cell for regulation of intestinal immune homeostasis. These results suggested that WBM reduces the inflammatory response and induces higher level of Treg cells in DSS-induced colitic mice. 
In summary, WBM enhanced Treg development in intestinal immune system in both in vitro and in vivo. The mechanism of enhancing Treg development by WBM are not only through AhR pathway, but also increased the CD103+ dendritic cells and IL-10 secretion. Furthermore, WBM inhibited the inflammatory response caused by colitis and induces higher level of Treg cells in the intestinal immune system. These results suggested that WBM could exert the anti-inflammatory and immunoregulatory effects in maintaining intestinal immune balance and alleviating the severity of the symptoms on inflammatory bowel disease.

参考文献 ( 229 ) 〈TOP〉

叶映君 (2009) 具降NF-κB转录活性之食材对高油饮食小鼠血糖及发炎介质的影响国立台湾大学微生物与生化学研究所硕士论文
连结：
康智雄 (2009) 影响3T3-L1细胞株分泌细胞激素之食材对高油饮食小鼠的免疫调节作用国立台湾大学微生物与生化学研究所硕士论文
连结：
吕学耘 (2010) 山苦瓜与共轭次亚麻油酸对气喘模式小鼠发炎与过敏免疫反应的影响国立台湾大学微生物与生化学研究所硕士论文
连结：
蔡侑伦 (2013) 以急性发炎小鼠模式探讨山苦瓜及其乙酸乙酯萃物对血清及肝脏发炎指标的影响国立台湾大学生化科技学系硕士论文
连结：
Abdullah, M., Chai, P. S., Loh, C. Y., Chong, M. Y., Quay, H. W., Vidyadaran, S., Seman, Z., Kandiah, M., Seow, H. F. (2011). Carica papaya increases regulatory T cells and reduces IFN-gamma+ CD4+ T cells in healthy human subjects. Mol Nutr Food Res, 55(5), 803-806.
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引用含有DOI的文献

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。 如想对DOI的使用与概念有进一步了解，请参考 （ ） 。

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。如想对DOI的使用与概念有进一步了解，请参考（）。