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. CONCLUSION: PTRF is a crucial regulator of TLR4 signaling in the development of sepsis.
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. CONCLUSION:PTRF is a crucial regulator of TLR4 signaling in the development of sepsis.
Authors: R Ogawa; R Pacelli; M G Espey; K M Miranda; N Friedman; S M Kim; G Cox; J B Mitchell; D A Wink; A Russo Journal: Free Radic Biol Med Date: 2001-02-01 Impact factor: 7.376
Authors: Meng Zhang; Seon-Jin Lee; ChangHyeok An; Jin-fu Xu; Bharat Joshi; Ivan R Nabi; Augustine M K Choi; Yang Jin Journal: Free Radic Biol Med Date: 2011-03-05 Impact factor: 7.376
Authors: Yingying Fu; Zhongyi Wang; Bing Lu; Siyan Zhao; Yi Zhang; Zongzheng Zhao; Chunmao Zhang; Jiaming Li; Bo Zhou; Zhendong Guo; Jun Qian; Linna Liu Journal: J Int Med Res Date: 2018-10-03 Impact factor: 1.671