Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary Sciences, Pennsylvania State University, 309A Life Sciences Building, University Park, PA 16802, USA.
J Pharmacol Exp Ther. 2012 Aug;342(2):345-55. doi: 10.1124/jpet.112.193482. Epub 2012 May 2.
Modulation of aryl hydrocarbon receptor (AHR) activity by a class of ligands termed selective AHR modulators (SAhRMs) has been demonstrated to attenuate proinflammatory gene expression and signaling, including repression of cytokine-mediated induction of acute-phase genes (e.g., Saa1). These effects are observed to occur through an AHR-dependent mechanism that does not require canonical signaling through dioxin response elements. Previously, we have demonstrated that the SAhRM 3',4'-dimethoxy-α-naphthoflavone (DiMNF) can repress the cytokine-mediated induction of complement factor genes. Here, we report that the activation of the AHR with DiMNF can suppress cytokine-mediated induction of the membrane complement regulatory protein CD55. When CD55 is expressed on host cells, it facilitates the decay of the complement component 3 (C3) convertase, thereby protecting the cell from complement-mediated lysis. Tumor cells often exhibit elevated CD55 expression on the cell surface in the inflammatory microenvironment of the tumor, and such enhanced expression could represent a means of escaping immune surveillance. DiMNF can repress the cytokine-mediated induction of CD55 mRNA and protein. Luciferase reporter analysis has identified possible response elements on the CD55 promoter, which may be targets for this repression. A C3 deposition assay with [(125)I]C3 revealed that repression of cytokine-mediated CD55 expression by DiMNF led to an increase of C3 deposition on the surface of Huh7 cells, which would likely stimulate the formation of the membrane attack complex. These results suggest that SAhRMs such as DiMNF have therapeutic potential in regulating the immune response to tumor formation.
芳基烃受体 (AHR) 活性的调制已被证明通过一类被称为选择性 AHR 调节剂 (SAhRMs) 的配体来实现，从而减轻促炎基因表达和信号转导，包括细胞因子介导的急性期基因（如 Saa1）的诱导抑制。这些效应被观察到通过一种不依赖二恶英反应元件的经典信号传导的 AHR 依赖性机制发生。先前，我们已经证明了 SAhRM 3'，4'-二甲氧基-α-萘黄酮（DiMNF）可以抑制细胞因子介导的补体因子基因的诱导。在这里，我们报告说，DiMNF 激活 AHR 可以抑制细胞因子介导的膜补体调节蛋白 CD55 的诱导。当 CD55 在宿主细胞上表达时，它促进补体成分 3 (C3) 转化酶的衰减，从而保护细胞免受补体介导的裂解。肿瘤细胞在肿瘤的炎症微环境中经常在细胞表面表现出升高的 CD55 表达，这种增强的表达可能代表逃避免疫监视的一种手段。DiMNF 可以抑制细胞因子介导的 CD55 mRNA 和蛋白的诱导。荧光素酶报告基因分析已经确定了 CD55 启动子上的可能反应元件，这些元件可能是这种抑制的靶标。[(125)I]C3 的 C3 沉积测定表明，DiMNF 抑制细胞因子介导的 CD55 表达导致 C3 在 Huh7 细胞表面的沉积增加，这可能会刺激膜攻击复合物的形成。这些结果表明，DiMNF 等 SAhRMs 在调节肿瘤形成的免疫反应方面具有治疗潜力。
