title: A novel 1,2-benzenediamine derivative FC-99 suppresses TLR3 expression and ameliorates disease symptoms in a mouse model of sepsis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  FC-99 reversed TLR3 expression and ameliorate CLP-induced sepsis in mice. Thus, FC-99 will be a potential therapeutic candidate for sepsis.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.forename: Erling
authors.initials: E
authors.lastname: Hu
authors.forename: Huan
authors.initials: H
authors.lastname: Dou
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Song
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.forename: Jianjian
authors.initials: J
authors.lastname: Ji
authors.forename: Erguang
authors.initials: E
authors.lastname: Li
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
mesh_terms: D000476:Alkanesulfonates / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D002432:Cecum / Q000601:surgery; D002460:Cell Line; D005466:Fluorocarbons / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D012136:Respiratory Syncytial Viruses / Q000187:drug effects / Q000502:physiology; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000476:Alkanesulfonates; D005466:Fluorocarbons; D015850:Interleukin-6; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; C051585:Fluorad FC99