title: Suppression of PTRF alleviates the polymicrobial sepsis induced by cecal ligation and puncture in mice.
abstract: BACKGROUND
  Sepsis and sepsis-associated organ failure are devastating conditions. Understanding the detailed cellular/molecular mechanisms involved in sepsis should lead to the identification of novel therapeutic targets.
  
  
  METHODS
  Cecal ligation and puncture (CLP) was used as a polymicrobial sepsis model in vivo to determine mortality and end-organ damage. Macrophages were adopted as the cellular model in vitro for mechanistic studies.
  
  
  RESULTS
  PTRF+/- mice survived longer and suffered less organ damage after CLP. Reductions in nitric oxide (NO) and iNOS biosynthesis were observed in plasma, macrophages, and vital organs in the PTRF+/- mice. Using an acute sepsis model after CLP, we found that iNOS-/- mice had a comparable level of survival as the PTRF+/- mice. Similarly, polymerase I transcript release factor (PTRF) deficiency resulted in decreased iNOS and NO/ROS production in macrophages in vitro. Mechanistically, lipopolysaccharide (LPS) enhanced the co-localization and interaction between PTRF and TLR4 in lipid rafts. Deletion of PTRF blocked formation of the TLR4/Myd88 complex after LPS. Consistent with this, lack of PTRF impaired the TLR4 signaling, as shown by the decreased p-JNK, p-ERK, and p-p38, which are upstream factors involved in iNOS transcription.
  
  
  CONCLUSIONS
  PTRF is a crucial regulator of TLR4 signaling in the development of sepsis.
authors.affiliation: Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Zheng
authors.forename: Seonjin
authors.initials: S
authors.lastname: Lee
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Liang
authors.forename: Shuquan
authors.initials: S
authors.lastname: Wei
authors.forename: Hyung-Geun
authors.initials: HG
authors.lastname: Moon
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D002432:Cecum / Q000276:immunology / Q000601:surgery*; D002460:Cell Line; D004195:Disease Models, Animal; D008026:Ligation; D008070:Lipopolysaccharides / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009569:Nitric Oxide / Q000032:analysis / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011677:Punctures; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D017384:Sequence Deletion; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C112745:Cavin1 protein, mouse; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: CLP; PTRF; ROS; TLR4; macrophage; nitric oxide; sepsis
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