Abstract
The innate inflammatory immune response must be tightly controlled to avoid damage to the host. Here, we showed that the tuberous sclerosis complex-mammalian target of rapamycin (TSC-mTOR) pathway regulated inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Inhibition of mTOR by rapamycin promoted production of proinflammatory cytokines via the transcription factor NF-kappaB but blocked the release of interleukin-10 via the transcription factor STAT3. Conversely, deletion of TSC2, the key negative regulator of mTOR, diminished NF-kappaB but enhanced STAT3 activity and reversed this proinflammatory cytokine shift. Rapamycin-hyperactivated monocytes displayed a strong T helper 1 (Th1) cell- and Th17 cell-polarizing potency. Inhibition of mTOR in vivo regulated the inflammatory response and protected genetically susceptible mice against lethal Listeria monocytogenes infection. These data identify the TSC2-mTOR pathway as a key regulator of innate immune homeostasis with broad clinical implications for infectious and autoimmune diseases, vaccination, cancer, and transplantation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Bacterial Agents / pharmacology
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Cytokines / biosynthesis
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Cytokines / immunology*
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Female
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Humans
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Immunity, Innate*
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Inflammation / immunology
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Inflammation / metabolism
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Lipopolysaccharides / immunology
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Listeria monocytogenes / immunology
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Listeriosis / immunology*
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Listeriosis / microbiology
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Listeriosis / prevention & control
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Monocytes / drug effects
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Monocytes / immunology*
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Monocytes / metabolism
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NF-kappa B / metabolism
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Protein Kinases / immunology
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Protein Kinases / metabolism*
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Th1 Cells / immunology
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Th1 Cells / metabolism
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Tuberous Sclerosis
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / metabolism*
Substances
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Anti-Bacterial Agents
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Cytokines
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Lipopolysaccharides
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NF-kappa B
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STAT3 Transcription Factor
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TSC2 protein, human
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Tsc2 protein, mouse
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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TOR Serine-Threonine Kinases
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Sirolimus