mTORC1-S6K activation by endotoxin contributes to cytokine up-regulation and early lethality in animals.

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.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.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.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Immunologi inom det medicinska området hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Immunology in the medical area hsv//eng
Animals
Cytokines
metabolism
Endotoxemia
metabolism
Endotoxins
metabolism
Extracellular Signal-Regulated MAP Kinases
metabolism
Lipopolysaccharides
metabolism
MAP Kinase Kinase 1
metabolism
Male
Mechanistic Target of Rapamycin Complex 1
Mice
Multiprotein Complexes
Mutation
Phosphorylation
Proteins
metabolism
Ribosomal Protein S6 Kinases
metabolism
Signal Transduction
TOR Serine-Threonine Kinases
Up-Regulation

Wilhelmson, Anna S KGothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för invärtesmedicin,Wallenberg Laboratory,Institute of Medicine, Department of Internal Medicine(Swepub:gu)xvilan (author)
Hubner, Anton P (author)
Reynolds, Samuel B (author)
Gallacchi, Dana A (author)
Chiou, Terry T (author)
Kwiatkowski, David J (author)
Göteborgs universitetWallenberglaboratoriet (creator_code:org_t)

By the author/editor: Lee, Po-Shun; Wilhelmson, Anna ...; Hubner, Anton P; Reynolds, Samuel ...; Gallacchi, Dana ...; Chiou, Terry T; show more...; Kwiatkowski, Dav ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Immunology in th ...

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