Kileng Øyvind, Albuquerque Artur, Robertsen Børre
Department of Marine Biotechnology, Norwegian College of Fishery Science, University of Tromsø, Breivika, N-9037 Tromsø, Norway.
Fish Shellfish Immunol. 2008 May;24(5):514-22. doi: 10.1016/j.fsi.2007.10.005. Epub 2007 Oct 25.
Imidazoquinolines represented by imiquimod and its derivative S-27609, have previously been shown to have potent antiviral and antitumor activity in several mammalian models. Much of the antiviral properties of imidazoquinolines have been ascribed to induction of IFN-alpha in peripheral blood mononuclear cells most notably plasmacytoid dendritic cells. Toll-like receptor (TLR) 7 has been identified as the receptor for imiquimod and S-27609 in mammals. In this work we show that S-27609 induces expression of IFN-alpha1/alpha2, Mx, ISG15 and IFN-gamma in organs of Atlantic salmon, which suggests that salmon responds to S-27609 through a TLR7-like receptor. The kinetics of gene expression in liver and head kidney induced by S-27609 was compared with that induced by the double-stranded RNA poly I:C, which is a ligand for TLR3 and the RNA helicase MDA5. In liver, S-27609 and poly I:C both induced transcripts for IFN-alpha1/alpha2, Mx and ISG15 with a peak at about 24h. In head kidney, poly I:C induced IFN-alpha1/alpha2 and Mx with one peak at about 24h. In contrast, S-27609 induced a biphasic increase of IFN-alpha1/alpha2 and Mx transcripts in head kidney with a minor peak at 14-24h and another increase starting at 72h. The other major difference in gene induction by the two stimulants was that S-27609 induced much lower levels of IFN-alpha1/alpha2 than poly I:C during the early time stages (14-48h) both in liver and head kidney. The difference in induction of IFN-alpha1/alpha2 by S-27609 and poly I:C may be a consequence of different cell targets for the two stimulants where S-27609 primarily induces IFNs through immune cells whereas poly I:C induces IFNs in most nucleated cells.
以咪喹莫特及其衍生物S - 27609为代表的咪唑喹啉类化合物，此前已在多种哺乳动物模型中显示出强大的抗病毒和抗肿瘤活性。咪唑喹啉类化合物的大部分抗病毒特性归因于其在外周血单核细胞（最显著的是浆细胞样树突状细胞）中诱导α干扰素。Toll样受体（TLR）7已被确定为哺乳动物中咪喹莫特和S - 27609的受体。在这项研究中，我们表明S - 27609可诱导大西洋鲑鱼器官中α干扰素1/α干扰素2、Mx、ISG15和γ干扰素的表达，这表明鲑鱼通过类似TLR7的受体对S - 27609产生反应。将S - 27609诱导肝脏和头肾中基因表达的动力学与双链RNA聚肌胞苷酸（poly I:C）诱导的动力学进行了比较，聚肌胞苷酸是TLR3和RNA解旋酶MDA5的配体。在肝脏中，S - 27609和聚肌胞苷酸均诱导α干扰素1/α干扰素2、Mx和ISG15的转录本，在约24小时达到峰值。在头肾中，聚肌胞苷酸诱导α干扰素1/α干扰素2和Mx，在约24小时出现一个峰值。相比之下，S - 27609在头肾中诱导α干扰素1/α干扰素2和Mx转录本呈双相增加，在14 - 24小时出现一个小峰值，另一个增加从72小时开始。这两种刺激剂在基因诱导方面的另一个主要差异是，在早期阶段（14 - 48小时），S - 27609在肝脏和头肾中诱导的α干扰素1/α干扰素2水平均远低于聚肌胞苷酸。S - 27609和聚肌胞苷酸在诱导α干扰素1/α干扰素2方面的差异可能是由于两种刺激剂的不同细胞靶点导致的，其中S - 27609主要通过免疫细胞诱导干扰素，而聚肌胞苷酸在大多数有核细胞中诱导干扰素。
