Dietary Ligands of the Aryl Hydrocarbon Receptor Induce Anti-Inflammatory and Immunoregulatory Effects on Murine Dendritic Cells
Dietary Ligands of the Aryl Hydrocarbon Receptor Induce Anti-Inflammatory and Immunoregulatory Effects on Murine Dendritic Cells
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DOI：
10.1093/toxsci/kfr249
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发表时间：
2011-12-01
影响因子：
3.8
通讯作者：
Shepherd, David M.
中科院分区：
文献类型：
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作者：
Benson, Jenna M.;Shepherd, David M.
免疫细胞如树突状细胞（DC）中芳烃受体（AhR）的活化可导致免疫应答受抑制。虽然AhR激活是最公认的介导其原型配体2，3，7，8-四氯二苯并-p-二恶英（TCDD）的影响，许多化合物存在于饮食来源也可以结合AhR。由于吲哚-3-甲醇（I3 C）和靛玉红-3 '-肟（IO）的免疫调节作用尚未在DC中研究，我们评估了这些化合物对小鼠DC的潜在免疫调节作用。我们假设I3 C和IO抑制DC中的免疫和炎症反应。我们发现，I3 C和IO都降低了CD 11 c、CD 40和CD 54的表达，而增加了MHC 2和CD 80的表达。在脂多糖（LPS）激活后，I3 C和IO抑制促炎介质的产生，包括肿瘤坏死因子-α、白细胞介素（IL）-1 β、IL-6、IL-12和一氧化氮，但增加IL-10水平。I3 C和IO的这些作用部分由AhR介导。此外，免疫调节基因，如ALDH 1A，IDO和TGFB，在用I3 C或IO处理后上调。I3 C和IO均降低核因子-κ B p65的基础水平，但仅I3 C抑制LPS诱导的RelB活性。最后，当与初始T细胞一起培养时，用饮食AhR配体处理的骨髓来源的树突状细胞以抗原特异性方式增加Foxp 3 + TcB的频率。总之，这些结果表明，I3 C和IO对DC表现出免疫抑制和抗炎作用。由于I3 C和IO的毒性明显低于TCDD，这些天然产物最终可能成为治疗自身免疫性和炎症性疾病的有用治疗剂。
Activation of the aryl hydrocarbon receptor (AhR) in immune cells, such as dendritic cells (DCs), can lead to suppressed immune responses. Although AhR activation is most recognized for mediating the effects of its prototypical ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), many compounds existing in dietary sources can also bind the AhR. Because the immunomodulatory effects of indole-3-carbinol (I3C) and indirubin-3'-oxime (IO) have yet to be investigated in DCs, we evaluated the potential immunomodulatory effects of these compounds on murine DCs. We hypothesized that I3C and IO suppress immune and inflammatory responses in DCs. We found that both I3C and IO decreased the expression of CD11c, CD40, and CD54 while they increased expression of MHC2 and CD80. Following lipopolysaccharide (LPS)-activation, I3C and IO suppressed the production of pro-inflammatory mediators including tumor necrosis factor-alpha, interleukin (IL)-1 beta, IL-6, IL-12, and nitric oxide but increased IL-10 levels. These effects of I3C and IO were partially mediated by the AhR. Additionally, immunoregulatory genes, such as ALDH1A, IDO and TGFB, were upregulated following treatment with I3C or IO. Both I3C and IO decreased basal levels of nuclear factor-kappa B p65, but only I3C suppressed the LPS-induced activity of RelB. Finally, when cultured with naive T cells, bone marrow-derived dendritic cells treated with the dietary AhR ligands increased the frequency of Foxp3+ Tregs in an antigen-specific manner. Taken together, these results indicate that I3C and IO exhibit immunosuppressive and anti-inflammatory effects on DCs. Because I3C and IO are significantly less toxic than TCDD, these natural products may ultimately become useful therapeutics for the treatment of autoimmune and inflammatory diseases.