Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells

The mammalian target of rapamycin (mTOR) can be viewed as cellular master complex scoring cellular vitality and stress. Whether mTOR controls also innate immune-defenses is currently unknown. Here we demonstrate that TLR activate mTOR via phosphoinositide 3-kinase/Akt. mTOR physically associates wit...

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Bibliographic Details
Published in:European journal of immunology 2008-11, Vol.38 (11), p.2981-2992
Main Authors: Schmitz, Frank, Heit, Antje, Dreher, Stefan, Eisenächer, Katharina, Mages, Jörg, Haas, Tobias, Krug, Anne, Janssen, Klaus-Peter, Kirschning, Carsten J, Wagner, Hermann
Format: Article
Language:English
Subjects:
Animals
Caspase 1 - physiology
Caspase‐1
Cells, Cultured
Cytokines - biosynthesis
Female
Humans
Immunity, Innate
Interferon Regulatory Factor-7 - physiology
Interleukin-1beta - biosynthesis
IRF
Lipopolysaccharides - toxicity
Mice
Mice, Inbred C57BL
mTOR
Protein Kinases - physiology
Signal Transduction
TLR
Toll-Like Receptors - physiology
TOR Serine-Threonine Kinases
Transcription, Genetic
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Summary:The mammalian target of rapamycin (mTOR) can be viewed as cellular master complex scoring cellular vitality and stress. Whether mTOR controls also innate immune-defenses is currently unknown. Here we demonstrate that TLR activate mTOR via phosphoinositide 3-kinase/Akt. mTOR physically associates with the MyD88 scaffold protein to allow activation of interferon regulatory factor-5 and interferon regulatory factor-7, known as master transcription factors for pro-inflammatory cytokine- and type I IFN-genes. Unexpectedly, inactivation of mTOR did not prevent but increased lethality of endotoxin-mediated shock, which correlated with increased levels of IL-1β. Mechanistically, mTOR suppresses caspase-1 activation, thus inhibits release of bioactive IL-1β. We have identified mTOR as indispensable component of PRR signal pathways, which orchestrates the defense program of innate immune cells.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.200838761