Gong Wei, Hu Erling, Dou Huan, Song Yuxian, Yang Liu, Ji Jianjian, Li Erguang, Tan Renxiang, Hou Yayi
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.
Br J Pharmacol. 2014 Nov;171(21):4866-78. doi: 10.1111/bph.12797. Epub 2014 Sep 23.
Sepsis is a clinical condition characterized by overwhelming systemic inflammation with high mortality rate and high prevalence, but effective treatment is still lacking. Toll-like receptor 3 (TLR3) is an endogenous sensor, thought to regulate the amplification of immune response during sepsis. Modulators of TLR3 have an advantage in the treatment of sepsis. Here, we aimed to explore the mechanism of a monosubstituted 1,2-benzenediamine derivative FC-99 {N(1) -[(4-methoxy)methyl]-4-methyl-1,2-benzenediamine}on modulating TLR3 expression and its therapeutic potential on mouse model of sepsis.
Cells were pretreated with FC-99 followed by poly(I:C) or IFN-α stimulation; TLR3 and other indicators were assayed. Female C57BL/6 mice were subjected to sham or caecal ligation puncture (CLP) surgery after i.p. injection of vehicle or FC-99; serum and tissues were collected for further experiments.
FC-99 suppressed inflammatory response induced by poly(I:C) with no effect on cell viability or uptake of poly(I:C). FC-99 also inhibited TLR3 expression induced by not only poly(I:C) but also by exogenous IFN-α. This inhibition of FC-99 was related to the poly(I:C)-evoked IRF3/IFN-α/JAK/STAT1 signalling pathway. In CLP-induced model of sepsis, FC-99 administration decreased mice mortality and serum levels of inflammatory factors, attenuated multiple organ dysfunction and enhanced bacterial clearance. Accordingly, systemic and local expression of TLR3 was reduced by FC-99 in vivo.
FC-99 reversed TLR3 expression and ameliorate CLP-induced sepsis in mice. Thus, FC-99 will be a potential therapeutic candidate for sepsis.
脓毒症是一种以全身性炎症反应过度为特征的临床病症，死亡率高且患病率高，但仍缺乏有效的治疗方法。Toll样受体3（TLR3）是一种内源性传感器，被认为在脓毒症期间调节免疫反应的放大。TLR3调节剂在脓毒症治疗中具有优势。在此，我们旨在探讨单取代1,2 - 苯二胺衍生物FC - 99{N(1)-[(4 - 甲氧基)甲基]-4 - 甲基 - 1,2 - 苯二胺}调节TLR3表达的机制及其对脓毒症小鼠模型的治疗潜力。
细胞先用FC - 99预处理，然后用聚肌胞苷酸（poly(I:C)）或干扰素 - α（IFN - α）刺激；检测TLR3及其他指标。雌性C57BL/6小鼠腹腔注射溶剂或FC - 99后进行假手术或盲肠结扎穿孔（CLP）手术；收集血清和组织用于进一步实验。
FC - 99抑制了poly(I:C)诱导的炎症反应，对细胞活力或poly(I:C)的摄取无影响。FC - 99还抑制了不仅由poly(I:C)而且由外源性IFN - α诱导的TLR3表达。FC - 99的这种抑制作用与poly(I:C)引发的IRF3/IFN - α/JAK/STAT1信号通路有关。在CLP诱导的脓毒症模型中，给予FC - 99可降低小鼠死亡率和炎症因子血清水平，减轻多器官功能障碍并增强细菌清除。相应地，FC - 99在体内降低了TLR3的全身和局部表达。
FC - 99可逆转TLR3表达并改善CLP诱导的小鼠脓毒症。因此，FC - 99将是脓毒症的一种潜在治疗候选药物。
