title: mTORC1-S6K activation by endotoxin contributes to cytokine up-regulation and early lethality in animals.
abstract: BACKGROUND
  mTORC1 (mammalian target of rapamycin complex 1) activation has been demonstrated in response to endotoxin challenge, but the mechanism and significance are unclear. We investigated the effect of mTORC1 suppression in an animal model of endotoxemia and in a cellular model of endotoxin signaling.
  
  
  RESULTS
  Mice were treated with the mTORC1 inhibitor rapamycin or vehicle prior to lethal endotoxin challenge. Mortality and cytokine levels were assessed. Cultured macrophage-like cells were challenged with endotoxin with or without inhibitors of various pathways known to be upstream of mTORC1. Activated pathways, including downstream S6K pathway, were assessed by immunoblots. We found that mTORC1-S6K suppression by rapamycin delayed mortality of mice challenged with lethal endotoxin, and was associated with dampened circulating levels of VEGF, IL-1β, IFN-γ and IL-5. Furthermore, in vitro cellular studies demonstrated that LPS (lipopolysaccharide) activation of mTORC1-S6K still occurs in the presence of PI3K-Akt inhibition alone, but can be suppressed by concurrent inhibition of PI3K-Akt and MEK-ERK pathways.
  
  
  CONCLUSIONS
  We conclude that cellular activation of mTORC1-S6K contributes to cytokine up-regulation and mortality in response to endotoxin, and may occur via multiple pathways.
authors.affiliation: Translational Medicine Division, Brigham & Women's Hospital, Boston, Massachusetts, United States of America. plee@rics.bwh.harvard.edu
authors.forename: Po-Shun
authors.initials: PS
authors.lastname: Lee
authors.forename: Anna S K
authors.initials: AS
authors.lastname: Wilhelmson
authors.forename: Anton P
authors.initials: AP
authors.lastname: Hubner
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Reynolds
authors.forename: Dana A
authors.initials: DA
authors.lastname: Gallacchi
authors.forename: Terry T
authors.initials: TT
authors.lastname: Chiou
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D019446:Endotoxemia / Q000378:metabolism*; D004731:Endotoxins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009154:Mutation; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D004731:Endotoxins; D008070:Lipopolysaccharides; D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1