Kim Woo Sik, Song Ha-Yeon, Mushtaq Sajid, Kim Jin-Man, Byun Eui-Hong, Yuk Jae-Min, Byun Eui-Baek
Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea.
Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
Cell Physiol Biochem. 2019;52(5):1117-1138. doi: 10.33594/000000076.
BACKGROUND/AIMS: New therapeutic strategies and the development of treatments against inflammatory bowel disease (IBD) require the initiation of immune tolerance and inhibition of excessive inflammation. Resveratrol, a polyphenolic compound, is a powerful immunosuppressor, but it can lead to apoptotic death of normal cells at high concentrations. When we induced a structural modification of resveratrol by gamma irradiation, we were able to investigate the potential tolerogenic and anti-inflammatory effect of a new radiolysis product (named γ-Res) during dendritic cell (DC) activation/differentiation.
The potential tolerogenic and anti-inflammatory effect of γ-Res were investigated by cytokine secretion, surface molecule expression, antigen uptake ability, antigen presenting ability, signaling pathway, and mixed lymphocyte reaction (MLR) assay using enzyme-linked immunosorbent assay (ELISA), western blot and flow cytometry.
LPS-activated DCs treated with γ-Res exhibited alterations in their mature and functional statuses including a strongly inhibited cytokine production, surface molecule expression, antigen-presenting ability, and activated DC-induced T cell proliferation/activation. In addition, the DCs generated by the γ-Res treatment during DC differentiation induced a decreased surface molecule expression and increased IL-10 production without altering the levels of TNF-α and IL-12p70, thereby promoting the inhibition of T cell proliferation/activation and the induction of regulatory T cells via interaction with DCs in vitro. Furthermore, in the in vivo DSS-induced colitis model, γ-Res treatment conferred protective immunity with a decrease in IFN-γCD4 and IL-17ACD4 T cells and imparted protection by reducing the disease activity and histological disease score and increasing the survival rate in dextran sulfate sodium (DSS)-induced colitis in mice.
Thus, our results suggest that γ-Res may be an excellent candidate for use in IBD treatment.
背景/目的：针对炎症性肠病（IBD）的新治疗策略和疗法的开发需要启动免疫耐受并抑制过度炎症。白藜芦醇是一种多酚化合物，是一种强大的免疫抑制剂，但高浓度时会导致正常细胞凋亡死亡。当我们通过γ射线辐照诱导白藜芦醇的结构修饰时，我们能够研究一种新的辐射分解产物（命名为γ-Res）在树突状细胞（DC）激活/分化过程中的潜在致耐受性和抗炎作用。
使用酶联免疫吸附测定（ELISA）、蛋白质印迹和流式细胞术，通过细胞因子分泌、表面分子表达、抗原摄取能力、抗原呈递能力、信号通路和混合淋巴细胞反应（MLR）测定来研究γ-Res的潜在致耐受性和抗炎作用。
用γ-Res处理的LPS激活的DC在其成熟和功能状态上表现出改变，包括细胞因子产生、表面分子表达、抗原呈递能力受到强烈抑制，以及激活的DC诱导的T细胞增殖/激活受到抑制。此外，在DC分化过程中用γ-Res处理产生的DC诱导表面分子表达降低和IL-10产生增加，而不改变TNF-α和IL-12p70水平，从而通过在体外与DC相互作用促进T细胞增殖/激活的抑制和调节性T细胞的诱导。此外，在体内DSS诱导的结肠炎模型中，γ-Res处理赋予保护性免疫，IFN-γ CD4和IL-17A CD4 T细胞减少，并通过降低疾病活性和组织学疾病评分以及提高葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎的存活率来提供保护。
因此，我们的结果表明γ-Res可能是用于IBD治疗的极佳候选物。
